Role of the GATA Family of Transcription Factors in Endocrine Development, Function, and Disease

Ontogeny-Reproduction Research Unit (R.S.V., S.M.G.), CHUQ Research Centre, Quebec City, Canada G1V 4G2; Centre de Recherche en Biologie de la Reproduction (R.S.V.), Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Canada G1V 0A6; Department of Obstetrics and Gynecology and Women's Health Research Program (M.A.) and Children's Hospital and Women's Health Research Program (M.H.), Biomedicum Helsinki, University of Helsinki, FI-00014 Helsinki, Finland; and Department of Pediatrics (D.B.W., M.H.), Washington University and St. Louis Children's Hospital, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Robert S. Viger, Ph.D., Ontogeny-Reproduction, Room T1-49, CHUQ Research Centre, 2705 Laurier Boulevard, Quebec City, Quebec, Canada G1V 4G2. E-mail: ac.lavalu.luhcrc@regiv.trebor; or Markku Heikinheimo, M.D., Ph.D., Children's Hospital, P.O. Box 22, 00014, University of Helsinki, Helsinki, Finland. E-mail: if.iknisleh@omiehnikieh.ukkram.

Abstract

The WGATAR motif is a common nucleotide sequence found in the transcriptional regulatory regions of numerous genes. In vertebrates, these motifs are bound by one of six factors (GATA1 to GATA6) that constitute the GATA family of transcriptional regulatory proteins. Although originally considered for their roles in hematopoietic cells and the heart, GATA factors are now known to be expressed in a wide variety of tissues where they act as critical regulators of cell-specific gene expression. This includes multiple endocrine organs such as the pituitary, pancreas, adrenals, and especially the gonads. Insights into the functional roles played by GATA factors in adult organ systems have been hampered by the early embryonic lethality associated with the different Gata-null mice. This is now being overcome with the generation of tissue-specific knockout models and other knockdown strategies. These approaches, together with the increasing number of human GATA-related pathologies have greatly broadened the scope of GATA-dependent genes and, importantly, have shown that GATA action is not necessarily limited to early development. This has been particularly evident in endocrine organs where GATA factors appear to contribute to the transcription of multiple hormone-encoding genes. This review provides an overview of the GATA family of transcription factors as they relate to endocrine function and disease.

GATA FACTORS ARE a group of evolutionarily conserved transcriptional regulators that play crucial roles in the development and differentiation of all eukaryotic organisms. In vertebrates, the GATA family comprises six members (named GATA1 to -6) that can be separated into two subgroups based on spatial and temporal expression patterns. GATA1/2/3 are expressed in hematopoietic cell lineages and are essential for erythroid and megakaryocyte differentiation, the proliferation of hematopoietic stem cells, and the development of T lymphocytes (1). Their expression, however, is not limited to hematopoietic cells but is also present in the brain, spinal cord, and inner ear where they play important roles in the development of these structures (2,3,4). In contrast, the GATA4/5/6 proteins are mainly found in tissues of mesodermal and endodermal origin such as the heart, gut, and gonads (5). Disruption of the Gata4 and Gata6 genes in mice results in early embryo lethality due to defects in heart tube formation and extraembryonic endoderm development, respectively (6,7,8,9). Although loss of GATA5 function is not lethal, female Gata5-null mice exhibit genitourinary abnormalities (10). The physiological requirement for GATA function in humans is further supported by the more recent identification of GATA gene mutations associated with human diseases, such as dyserythropoietic anemia and thrombocytopenia (GATA1 mutation); hypoparathyroidism, deafness, and renal dysplasia (HDR syndrome; GATA3 mutation); and congenital heart defects (GATA4 mutation) (11,12,13).

All vertebrate GATA proteins contain a conserved DNA-binding domain composed of two multifunctional zinc fingers involved in DNA-binding and protein-protein interaction with other transcriptional partners and/or cofactors (Fig. 1 ​ 1). ). Because members of the GATA family share a highly conserved DNA-binding domain, there is an apparent redundancy in DNA binding properties to target GATA sequences (14,15). These in vitro properties contrast, however, with their often nonredundant roles in vivo (6,7,9,16,17,18). The specificity of GATA action is governed, in part, through protein-protein interactions with other transcriptional partners. Indeed, there is now an extensive list of ubiquitously expressed or cell-restricted factors that are known to cooperate with GATA factors to control tissue-specific transcription in the hematopoietic system, the heart, and many other tissues (19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45). The activity of GATA factors has also been shown to be modulated by posttranslational modifications such as sumoylation, acetylation, and phosphorylation. The effect of these modifications most often involves enhanced transcriptional activity due to changes in GATA nuclear localization, DNA-binding, protein stability, and/or cofactor recruitment (see Table 1 ​ 1 for references). With respect to endocrine cells, GATA4 phosphorylation has been the best studied posttranslational modification to date (described further below).

Structure and Homology of the Vertebrate GATA Proteins

All GATA factors share a similar zinc finger DNA-binding domain, a feature that defines this family of transcription factors. The zinc finger (ZnF) region is also involved in protein interactions with cofactors and/or other transcriptional partners. Transactivation domains are located in the N-terminal (N-term) and C-terminal (C-term) regions. The percent homology among the different GATA proteins (as deduced from the mouse sequences) in the N-terminal, C-terminal, and zinc finger domains is indicated. NLS, Nuclear localization signal.

Table 1

Posttranslational Modifications of GATA Factors

Although originally classified as markers of hematopoietic and cardiac cells, the expression pattern and functions attributed to GATA factors extend well beyond these cell lineages. Interestingly, GATA factors have been described in most, if not all, of the endocrine organs where they are emerging as important regulators of numerous genes coding for hormones or proteins/enzymes involved in hormone biosynthesis. A comprehensive list of putative GATA-regulated genes in endocrine tissues is presented in Table 2 ​ 2. . In the sections that follow, our current understanding of the expression and role of GATA factors in different endocrine organs is presented.

Table 2

Putative GATA Target Genes in Endocrine Tissues

e, EMSA and/or DNA footprinting; t, transfection data; c, ChIP; g, genetic (mouse) data; s, small interfering RNA-mediated knockdown data.

GATA FACTORS IN ENDOCRINE TISSUES

Hypothalamus and Pituitary

The expression of Gata4 in migrating GnRH neurons at embryonic d 13.5 (e13.5) but not in mature GnRH-secreting neurons in mouse has led to the hypothesis that GATA factors could play a role in the differentiation of the small population of neurosecretory cells that mediate central nervous system control of reproduction (46). In hypothalamic neuronal GT1-7 cells, GATA4 activates GnRH (Gnrh1) transcription through binding to two GATA motifs arranged in tandem repeat within the GnRH neuron-specific enhancer (46). Because the GATA-binding site is also involved in Gnrh1 gene regulation in the mature hypothalamus, the role for GATA in Gnrh1 expression would not appear to be limited to cell differentiation. The absence of GATA4 binding activity in adult hypothalamus nuclear extracts does not exclude the possibility of the binding of another, yet to be identified, GATA family member or some other transcriptional regulator (46).

The mature pituitary gland orchestrates the homeostasis of key endocrine organs by regulating their function in response to signals coming from brain and the periphery. Among the six adult differentiated hormone-secreting cell types, both thyrotrope and gonadotrope cells express GATA2 from e10.5 onward, whereas GATA3 is transiently expressed during development (47). The secretory products of thyrotrope and gonadotrope cells are heterodimers that share a common α-glycoprotein subunit (αGSU) and a specific β-subunit (FSHβ, LHβ, and thyrotropin-β). Interestingly, genes encoding αGSU (Cga) and thyrotropin-β (Tshb) are GATA2 target genes (21,48,49). Moreover, although a functional GATA binding site has been described in the GnRH receptor promoter in pituitary cells, the GATA factor that binds has not yet been identified (50).

GATA2 is involved in both gonadotrope and thyrotrope terminal cell specification. The detailed analysis of several transgenic mouse models such as expression of a dominant-negative form of GATA2 under the control of Cga (αGSU) regulatory sequences and overexpression of GATA2 directed by the Pou1f1 (Pit1) promoter, have highlighted the complex mechanisms whereby interactions between Pit1 and GATA2 contribute to pituitary cell fate determination (47,51). In gonadotropes where GATA2 is expressed in the absence of Pit1, GATA2 promotes the expression of gonadotrope-specific genes. In thyrotropes, where GATA2 and Pit1 are coexpressed, thyrotrope-specific genes are up-regulated by the binding of both factors to adjacent DNA cis-elements, whereas GATA motif-containing gonadotrope-specific genes are down-regulated. This discrepancy comes from the ability of Pit1 to interact with a critical DNA-binding zinc finger of GATA2, via its homeodomain, thus preventing GATA2 DNA-binding and target gene transactivation (47). Because of the early embryonic lethality of Gata2-null mice resulting from severe anemia consistent with the critical role of GATA2 in both primitive hematopoiesis of the yolk sac and definitive hematopoiesis of the liver (18), the role of GATA2 in later development was obscured. However, a recent study reporting pituitary-specific Gata2 knockout mice has shed further light into its role in pituitary function (52). Loss of GATA2 in the anterior pituitary results in a decrease in gonadotrope and thyrotrope cell numbers at birth and a marked decrease in secretory capacity of these cells in the adult (52). Although Gata2 pituitary knockout mice have defects in the same pituitary cell populations as the dominant-negative GATA2 transgenic mice (47), the extent of the defect is much less severe (52). This difference has been proposed to be due to compensation by GATA3 that is up-regulated in the Gata2 pituitary knockout mice and that would normally be targeted by the GATA2 dominant-negative. Thus, GATA2 has been proposed to have a dual role in pituitary function: the initial specification and/or proliferation of thyrotropes and the later maintenance of hormone expression in mature thyrotropes and gonadotropes (52). Consistent with this hypothesis, GATA2 is found in most αGSU-positive and thyrotropin-secreting human pituitary adenomas (53).

Thyroid and Parathyroid

The parathyroid glands regulate calcium balance in the body through the secretion and action of PTH. Developmentally, parathyroid glands, together with the thyroid, thymus, and ultimobranchial bodies, originate from the pharyngeal region by the complex interactions between endoderm and neural crest derivatives (54). GATA3 expression has been reported in human embryos in the second and third branchial arches, from which the parathyroids derive (55). Although a consensus GATA binding site has been identified in the proximal promoter of the murine PTH (Pth) gene (56), its functional relevance remains unclear, and to date, no other potential GATA3 target genes have been identified in the developing parathyroid. Homozygous Gata3 knockout mice display mid-gestation lethality (16), in part due to a noradrenaline deficiency of the sympathetic nervous system, which can be rescued by pharmacological treatment with catechol intermediates (57). Because of this early embryonic lethality, the generation of parathyroid-conditional Gata3 transgenic mice would therefore be of particular interest to gain insights into the role of GATA3 in adult parathyroid gland physiology. However, the importance of GATA3 in parathyroid function has not come from transgenic mice but rather from study of patients suffering hypoparathyroidism, sensorineural deafness, and renal anomaly (HDR) syndrome. HDR syndrome has been linked to deletions or mutations of GATA3 that affect the integrity of its two zinc fingers (13,58,59,60,61,62,63). Whereas mutations involving the first zinc finger result in either a loss of interaction with Friend of GATA (FOG) transcriptional partners or altered DNA-binding affinity, those involving the GATA3 second zinc finger or adjacent basic amino acids result in a loss of DNA-binding (58). Although no GATA factor has yet been reported to regulate thyroid development, at least two thyroid-expressed genes, Nkx2–5 and Nkx2–1, have been shown to be under GATA control in the heart and lung, respectively (64,65). Therefore, a similar regulation in the thyroid would not be unlikely.

Pancreas

The mammalian pancreas is a mixed exocrine and endocrine gland that is formed from the fusion of dorsal and ventral buds of the foregut endoderm. In recent years, our understanding of pancreatic development has benefited from the identification of essential transcription factors implicated in this process such as pancreatic and duodenal homeobox 1 (PDX1) and neurogenin 3 (NEUROG3) (66,67). The cardiac subfamily of GATA factors are well-known markers of several endodermal derivatives including yolk sac, lung, stomach, gut, and pancreas (5). GATA4 and GATA6 have overlapping expression profiles in the early pancreas (68,69). GATA4 then becomes limited to exocrine tissue and GATA6 to a subpopulation of endocrine cells (68). GATA6, but not GATA4, has also been shown to interact with Nkx2.2 (68), a critical islet transcription factor. In the same study, transgenic mice expressing a GATA4- or GATA6-Engrailed dominant repressor fusion protein in the pancreatic epithelium and in the islet revealed an important role for GATA6, but not GATA4, in early pancreas specification (68). Expression of the GATA6-Engrailed transgene had two distinct phenotypes: agenesis of the pancreas or a reduction in pancreatic tissue. In the latter, all pancreatic cell types were significantly reduced, having few differentiated endocrine cells within enlarged ductal structures (68). In contrast to these findings, others have reported that GATA4 colocalizes with early glucagon-positive cells as early as e12.5 in the mouse and that GATA4 is able to transactivate the glucagon (Gcg) gene promoter in vitro (70). The same study also demonstrated that mutation of the GATA binding element in the Gcg promoter reduces its basal promoter activity in glucagon producing cells by 55%. In another study, the development of the ventral but not dorsal pancreas is completely absent in Gata4 −/− embryos, and Gata6 −/− embryos display a similar but less dramatic phenotype (71). GATA4 has been found to be frequently overexpressed and infrequently methylated in human pancreatic cancers, whereas GATA5 is likely hypermethylated during pancreatic cancer development (72).

Testis

Reproductive tissues are prominent sites of GATA expression. In the gonads, GATA-like proteins are evolutionarily conserved because they are found in a variety species ranging from worms to humans (73,74). In mammals, four GATA factors exhibit gonadal expression (GATA1/2/4/6), and with the exception of GATA2 (75), this expression is exclusive to the somatic cell population (73,74) (Fig. 2 ​ 2). ). The testis contains two major somatic cell types that facilitate spermatogenesis: Sertoli cells, which are the supporting cell lineage, and Leydig cells, the steroidogenic cell lineage. GATA factors have been described in both cell types in several species starting from the early stages of testis differentiation to adult cells (74). Sertoli cells express GATA4 from the onset of their differentiation through to adulthood where its level of expression is considered to be constant regardless of the stage of germ cell maturation (76,77,78,79,80,81,82,83). GATA6 is also present early and is maintained in adult Sertoli cells (78,80,84). Finally, a third GATA factor, GATA1, is expressed by Sertoli cells, but the temporal expression of GATA1 in this lineage differs from that of other GATA members. GATA1 is first detected in the immature animal in Sertoli cells of all the tubules, concomitantly with the first wave of spermatogenesis (83,85). In the adult animal, GATA1 expression in Sertoli cells in stages VI–IX of the seminiferous epithelium cycle coincides with the androgen-sensitive VII–VIII stages and appears to be dependent on the presence of maturing germ cells (79,85). Although both GATA4 and GATA6 have been described in Leydig cells (78,83,84), GATA4 is by far the predominant GATA factor of this cell type, especially in rodents. GATA4 has also been reported in Sertoli and Leydig cell tumors (86).

Expression of GATA Factors and Their FOG Cofactor Proteins during Gonadal and Adrenal Development

Contribution of cells from adrenogenital primordium and neural crest cells ultimately give rise to the cortex and medulla of the mature adrenal gland. The testis and ovary develop from a bipotential gonad common to both sexes. GATA factors and FOG2 exhibit overlapping expression patterns throughout development of these three endocrine organs (see text for references). #, Expression specific to cells of the adrenal medulla; *, expression in germ cells.

Because of the critical role of GATA factors in hematopoietic and cardiac development and the corresponding early embryonic lethality associated with Gata-null mice, alternative strategies have had to be developed to unravel their function in testis differentiation and physiology. Conditional knockout of GATA1 in Sertoli cells failed to yield a significant phenotype, most likely due to the redundancy of multiple GATA factors in this cell type (87). Other approaches, however, have begun to give clues into the roles of GATA4 in testis cell differentiation. For example, mice homozygous for a GATA4 variant that cannot interact with its cofactor FOG2 (Gata4 ki/ki ) or homozygous for a FOG2-null mutant (Fog2 −/− ) exhibit abnormal testis morphogenesis resulting from a failure of Sertoli cells to differentiate (88). On a molecular level, this appears to be due to a significant reduction in transcription of the testis-determining gene Sry (88), as well as a block in Sox9 expression (89,90). Whether Sry and Sox9 are direct targets of a GATA4/FOG2 complex, however, remains to be demonstrated. The Gata4 ki/ki and Fog2 −/− mice also fail to express anti-Müllerian hormone (Amh) as well as several steroidogenic markers [cytochrome P450 side chain cleavage (Cyp11a1), cytochrome P450 17α-hydroxylase/17,20 lyase (Cyp17a1), and 3β-hydroxysteroid dehydrogenase type 1 (Hsd3b1)], suggesting that steroidogenic cell differentiation and/or gene expression is equally under GATA4/FOG2 control (88). Indeed, a recent study using chimeric mice has shown that that GATA4 is directly required for Leydig cell differentiation in the fetal mouse testis (91). Additional indirect support for a role for GATA factors in Leydig cells has come from the characterization of GATA-like protein 1 [GLP1 (Glp1)] knockout mice (92). Glp1 is expressed in Leydig cells where it appears to act as a repressor of GATA action (92). In males, loss of GLP1 function correlates with an early impairment of germ cell differentiation, suggesting that a complex regulation of GATA proteins in Leydig cells by GLP1, FOG2, and perhaps other modulatory factors, is crucial for their function. Although these mouse studies have illustrated the involvement of GATA factors for early testis cell differentiation, other strategies are still needed for the direct assessment of their function in the mature testis.

Important insights into GATA function in the testis have also come from promoter studies of putative target genes in cell lines or primary cultures of Sertoli and Leydig cells. Most of these GATA gene targets are either correlated with early differentiation (Dmrt1, Sry, and Sox9), or hormone synthesis such as the inhibin subunits (Inha and Inhb), Amh, and multiple proteins and enzymes of the steroidogenic pathway in Leydig cells (see Table 2 ​ 2). ). Interestingly, recent studies have identified genes encoding junctional proteins such as claudin 11 and Coxsackie- and adenovirus receptor-like membrane protein (CLMP) as novel GATA targets in the testis (93,94). Although a scaffolding protein of the blood-testis barrier, Cldn11 expression has been shown to be under germ cell and androgen regulation (95,96), with the androgen regulation apparently mediated by GATA and NFYA proteins (94).

Despite the long list of target genes for GATA factors in testicular cells, we have only begun to scratch the surface as to how these factors are themselves regulated. At the transcriptional level, it is now evident that Gata1 expression in mouse Sertoli cells is dependent on a cell-specific promoter (97,98,99) and is negatively regulated by FSH and cAMP (100). In contrast to GATA1, gonadotropins and/or cAMP agonists have been shown to induce Gata4 and/or Gata6 expression in several gonadal cell lines, including MSC-1 Sertoli cells and mLTC-1 Leydig cells (78,101). The dissection of the Gata4 promoter has begun to reveal some of its transcriptional control mechanisms (102,103). In transgenic mice, the first 5 kb of the 5′-flanking region of the Gata4 gene is sufficient to recapitulate endogenous Gata4 expression in Sertoli cells throughout development (102). Subsequent in vitro studies identified two GC-box motifs and especially one E-box element within this −118-bp region that are crucial for Gata4 transcriptional activity in both testicular and cardiac cells (102,103). In Sertoli cells, members of the upstream transcription factor (USF) family of factors, especially USF2, bind to and activate the Gata4 promoter via this critical E-box motif (102). Gata4 regulatory sequences driving expression in steroidogenic (Leydig) cells of the testis and ovarian cells have yet to be identified.

In both Sertoli and Leydig cells, GATA4 activity is modulated via cooperative interactions with other transcriptional regulators and/or cofactors (73,74,104). These include the nuclear receptors steroidogenic factor 1 (SF-1/NR5A1) and liver receptor homolog 1 (LRH-1/NR5A2), which cooperate with GATA4 to enhance transcription from the Inha, Amh, P450 aromatase (Cyp19a1), and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) promoters (27,35,36,105). In testicular cells, GATA1 and GATA4 also interact with FOG1 and FOG2 (25,26,106). Although the FOG proteins do not bind directly to DNA, they function as either enhancers or repressors of GATA transcriptional activity depending on the cell and promoter context being studied (25,26,28,106,107,108,109). On GATA-dependent gonadal promoters, however, in vitro data suggest that FOG proteins play a strictly repressive role (110). In the mouse testis, FOG1 and FOG2 are coexpressed with GATA1/4/6 in Sertoli and Leydig cells (79,110). FOG1 is first detected in Sertoli cells at e15.5; expression is maintained throughout development but eventually becomes restricted to stage VII–XII tubules in the adult (79). FOG2 is expressed earlier than FOG1 and can be detected as early as the undifferentiated gonad stage in both sexes (76). After sex determination, testicular FOG2 expression is rapidly down-regulated by e15.5, leaving only the testis capsule and Leydig cells as significant sites of expression (79). FOG2 then reappears after birth and, like FOG1, eventually becomes restricted to stage VII–XI tubules in the adult testis (79). Different mouse models have clearly identified a role for a GATA4/FOG2 complex in early testis differentiation, acting upstream of Sry and Sox9 (88,89,90). However, it remains to be shown whether these genes and other GATA targets in the testis are directly modulated by either FOG-mediated coactivation or corepression.

GATA4 is also a target for posttranslational modifications such as phosphorylation (34,111,112,113,114,115,116,117). In gonadal cells, activation of the cAMP/protein kinase A (PKA) signaling pathway is a major mechanism for conveying the hormone responsiveness of many genes. In this classic pathway, PKA phosphorylates cAMP response element (CRE)-binding protein (CREB), which is then recruited along with the CREB-binding protein (CBP) coactivator to activate genes possessing CRE in their promoters. In MA-10 Leydig cells, GATA4 is directly phosphorylated by PKA on a specific serine residue (Ser261) (114). Phosphorylation of GATA4 allows for synergistic interactions with different transcription factors including CCAAT/enhancer-binding protein (C/EBPβ) and NR5A2 (34,35) and permits recruitment of the CBP transcriptional coactivator much like CREB (114). This leads to robust stimulation of transcription from gonadal promoters such as Star, Inha, and HSD3B2 (34,35,36,114). PKA is not the sole kinase known to target the GATA4 protein. Indeed, in the heart, phosphorylation of GATA4 at Ser105 via the MAPK signaling pathway plays a crucial role in modulating its GATA4 activity in cardiomyocytes (111,112,118). Although GATA4 Ser105 has been shown to be constitutively phosphorylated in porcine granulosa cells (119), and appears to contribute to the FSH-induced up-regulation of Cyp19a1 expression in these same cells in the rat (120), its significance in testicular cells remains to be demonstrated.

Ovary

The fetal ovary has been shown to express three GATA factors: GATA2, -4, and -6 (Fig. 2 ​ 2). ). In the mouse, GATA2 is specific for germ cells but only for a brief period during fetal development (e11.5–e15.5) (75). GATA4 is first detected in the mouse coelomic epithelium and porcine urogenital ridge of both XX and XY embryos (76,79,81,83). At this time, GATA4 and its cofactor FOG2 label the somatic cell population of the developing gonad (76,79). Subsequently, GATA4 and FOG2 continue to be expressed at high levels in ovarian somatic cells over the entire fetal period (76). GATA4 expression patterns are similar in the fetal rat and porcine ovary; the somatic, pregranulosa or follicular cells are GATA4 positive, whereas germ cells do not express this factor (80,81). In the fetal rat ovary, GATA6 is present in both postmitotic germ cells and the ovarian epithelium (80). In the human fetal ovary, GATA4 is strongly expressed in pregranulosa/stromal cells as early as gestational wk 13 and 14, when primordial follicles are not yet evident (121). By wk 16–33, GATA4 localizes to granulosa cells (121). Like GATA4, GATA6 and FOG2 are expressed in human fetal somatic cells but can also be detected in occasional germ cells (unpublished data). Thus, much like the testis, the abundant expression of GATA proteins, particularly GATA4, in the fetal ovary suggest that they play key roles in the early steps of ovarian differentiation.

In the postnatal ovary, GATA4 and GATA6 are the predominant GATA factors. GATA4 expression is negligible in primordial follicles of both the mouse and human ovary (76,80,101,122,123). GATA4 expression initiates in granulosa cells at the onset of follicle growth (i.e. their initial recruitment) and their transformation into primary follicles (76,101,122,123). As follicular growth proceeds, granulosa cells of healthy preantral and antral follicles express GATA4, where it localizes to cumulus and mural granulosa cells, theca cells, and stromal cells (76,80,101,122,123,124). In luteal glands, GATA4 expression is low or negligible in mice and humans (76,101,123). However, in the rat and pig, GATA4 is expressed in peripheral cells of new luteal glands; expression is down-regulated as these structures regress (80,124). Thus, GATA4 expression is clearly linked to both structural and functional changes in the postnatal ovary of different mammalian species. GATA6 is also expressed in multiple cell types of the mouse, pig, and human postnatal ovary. These include oocytes, luteal glands, and granulosa and theca cells of larger follicles (80,101,122,123,124). Whereas GATA4 expression in granulosa cells is usually down-regulated in follicles undergoing atresia, GATA6 expression in rodents is retained at this stage (80,101). In humans, GATA6 and FOG2 expression patterns are similar; primary follicles have negligible or weak immunoreactivity, but in later follicular stages, GATA6 and FOG2 proteins are detected in most granulosa cells, occasional oocytes, and luteal glands (122,123). In the mouse, only a few granulosa cells of primordial follicles readily express FOG2 protein. In antral follicles, FOG2 expression is often down-regulated, whereas GATA4 expression is retained (76).

Of the endocrine and paracrine regulators of folliculogenesis, gonadotropins as well as TGFβ signaling have been linked to the regulation of ovarian GATA function. Gonadotropins have a fundamental impact on ovarian folliculogenesis, especially FSH, which is required for the development from preantral to antral follicles (125). In FSH-unresponsive ovaries of women with an inactivating mutation in the FSH receptor gene (FSHR), GATA4 is absent in the large pool of primordial follicles as compared with healthy ovaries (126). However, granulosa cells in the few primary follicles seen in these patients do express GATA4 protein, suggesting that either FSH or FSH receptor is not required for the initial activation of GATA4 expression. In Fshr-null mice bearing follicular arrest at the preantral stage, Gata4 expression is, however, impaired in preantral follicles compared with age-matched wild-type animals (127). In vitro studies have further established the link between gonadotropins and the regulation of GATA4 and/or GATA6 action in the ovary. Like testicular cells (114), the transcriptional activity of GATA proteins is likely induced by FSH/cAMP/PKA-mediated phosphorylation in granulosa cells (124). In murine granulosa tumor cells, which resemble normal granulosa cells, FSH and forskolin up-regulate Gata4 mRNA levels (101). Moreover, treatment of immature 3-wk-old mice with pregnant mare serum gonadotropin (PMSG) enhances follicular expression of Gata4 and Gata6 transcripts (101). Similarly, in primary rat granulosa cells, FSH up-regulates GATA4 mRNA and protein levels (120), whereas in immature human granulosa cells, obtained from in vitro maturation of oocytes during fertility treatments, FSH was shown to up-regulate GATA6 mRNA levels (128). In cultured preovulatory human granulosa cells, which luteinize during in vitro culture, treatments with recombinant human chorionic gonadotropin or 8-Br-cAMP had no effect on GATA4 and FOG2 steady-state mRNA levels, whereas GATA6 mRNA levels were modestly but significantly up-regulated (123). The effects on GATA6 rather than GATA4 likely reflect the luteinized phenotype of human granulosa cells.

TGFβ regulation of GATA target genes has been previously demonstrated in both cardiac and T helper cells (129,130). Recent results also support a role for GATA4 in TGFβ signaling in the ovary. In mouse granulosa tumor cells TGFβ is able to up-regulate GATA4 protein levels (131). Furthermore, TGFβ activation of the Inha promoter, a GATA target in both the testis and ovary (Table 2 ​ 2), ), is blocked when the critical GATA binding sites are mutated (131). GATA4 interacts with Smad3 in granulosa tumor cells, suggesting a role for GATA4 in the transcriptional complex activated by the TGFβ-signaling pathway in the ovary. The proposed role for TGFβ and other signaling mechanisms in the regulation of GATA4 activity in gonadal cells is presented in Fig. 3 ​ 3 .

Involvement of Intracellular Signaling Mechanisms in the Regulation of GATA4 Activity in Gonadal Cells

In response to hormonal signals and/or growth factors, activation of the cAMP/PKA and MAPK signaling pathways leads to phosphorylation of GATA4 on specific serine residues: Ser261, a PKA target, and Ser105, a MAPK target. GATA4 phosphorylation increases its DNA-binding and transactivation properties on different gonadal promoters and enhances the ability of GATA4 to recruit and cooperate with different transcriptional partners such as SF-1 (NR5A1), liver receptor homolog 1 (LRH-1/NR5A2), CCAAT/enhancer-binding protein (C/EBPβ), and CBP. In murine and rat granulosa cells, signaling elicited by gonadotropins or TGFβ family members increases Gata4 transcription. TGFβ-mediated activation of Smad3 and its cooperation with GATA4 also leads to robust transcription of gonadal genes such as Inha (see text for references).

Much like the testis, important insights into the role of GATA factors in ovarian function have come from an analysis of potential target gene promoters in ovarian cells. Because somatic cells of both the ovary and testis express similar GATA proteins, it is not surprising that GATA factors have similar target genes in these two tissues (Table 2 ​ 2). ). To date, proposed GATA-dependent genes in the ovary include Star (132,133,134), GNRHR (135), Inha (131), Cyp19a1 (120,136,137), 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) (138), Cyp11a1 (139), and Bcl2 (unpublished data). One of the first GATA target genes to be described in gonadal cells was AMH (83). In vitro and in vivo studies have provided strong evidence that the mouse and human AMH promoter, at least in the testis, is an important target for GATA4 (140,141). Although exclusive to the fetal testis, the anti-Müllerian hormone (AMH) is nonetheless produced by granulosa cells of the postnatal ovary where GATA4 is also found (142). Therefore, a similar role for GATA4 in AMH gene regulation in the ovary is likely.

Placenta

GATA factors in placental cells were initially described in studies of αGSU (CGA) transcription in the human trophoblast-derived JEG-3 choriocarcinoma cell line (48). Nuclear extracts of JEG-3 cells were shown to contain GATA2 and GATA3 protein capable of binding to a consensus GATA motif in the proximal CGA promoter (48). Moreover, mutation of the αGSU GATA element dramatically reduced CGA promoter activity in JEG-3 cells, suggesting that GATA2 and/or GATA3 is an important contributor to CGA transcription in the placenta (48). Subsequent Northern blot and in situ hybridization studies revealed that the Gata2 and Gata3 transcripts are abundantly expressed in mouse placenta, localizing predominantly to trophoblast giant cells (143). In these cells, the murine or ovine genes encoding for the placental hormones placental lactogen 1 (PRL3D1) and proliferin (PRL2C2) have been proposed to be regulated by GATA2 and/or GATA3 (143,144,145). Indeed, although mice lacking either the Gata2 or Gata3 gene develop trophoblast giant cells, placental Prl3d1 expression is nonetheless reduced by 50% in these animals (145). For the Prl2c2 gene, a similar 50% reduction in expression was observed in Gata3-null placentas, and this reduction was even more pronounced (5- to 6-fold) in Gata2-null placentas (145). Proliferin is an angiogenic hormone known to stimulate endothelial cell migration and neovascularization of the placenta (146). Consistent with a role for GATA2 in Prl2c2 expression, decidual tissue adjacent to Gata2-null placentas has been reported to exhibit less neovascularization as compared with wild-type tissue (145).

In vitro studies have also identified other placenta-expressed gene promoters as potential targets for regulation by GATA or GATA-like factors. These include the mouse promoters for adenosine deaminase (Ada) (147) and Cyp11a1 (139) and the human promoters for leukemia inhibitory factor receptor (LIFR) (148), GnRH receptor (GNRHR) (149), (HSD17B1) (150), (HSD3B1) (151), and (CYP17A1) (38). Whether these genes are actual targets in vivo, however, awaits further genetic studies.

Adrenal

The adrenal cortex arises from mesodermal precursors that also give rise to gonadal steroidogenic cells (152). The human fetal adrenal cortex consists of a large inner zone, termed the fetal zone, and a thin outer rim of more immature cells, known as the definitive zone (152). After birth, the fetal zone regresses. In late gestation, the definitive zone begins to partition into anatomically and functionally distinct compartments: the zona glomerulosa, zona fasiculata, and zona reticularis (152). In the mouse adrenal, the zona glomerulosa and zona fasciculata are well defined, but there is no discernable zona reticularis. The adrenal cortex of the young mouse contains an additional layer, termed the x-zone, which is adjacent to the medulla and is analogous to the fetal zone of the human adrenal cortex (153).

GATA6 is abundantly expressed in the adrenal cortex throughout development (38,154,155). During human fetal development, GATA6 is evident in both the fetal and definitive zones of the adrenal cortex (154). In the adult, GATA6 is expressed in the zona reticularis and to a lesser extent the zona fasciculata (154,156,157), but its pattern of expression during early childhood and adrenarche has not been established. Based on this distribution and promoter analyses described below, GATA6 is postulated to play a key role in the production of adrenal androgens and possibly also glucocorticoids (156). In the mouse, GATA6 is expressed in both the fetal and adult adrenal cortex (154), suggesting a role beyond merely adrenal androgen biosynthesis. Although evidence for the involvement of GATA6 in adrenal steroidogenesis is accumulating, genetic proof that GATA6 is required for adrenocortical function is lacking.

By comparison, GATA4 has a more restricted pattern of expression during adrenocortical development and therefore is presumed to have a limited role in the function of this tissue (154). During human development, GATA4 mRNA is evident in the fetal zone of the adrenal, but there is only weak expression of this transcript in the adrenal cortex postnatally (154). Similarly, Gata4 is transiently expressed in the mouse adrenal cortex during fetal but not postnatal development (154), a pattern reminiscent of Cyp17a1 in the mouse (158). Given their overlapping patterns of expression, it is possible that GATA4 enhances expression of Cyp17a1 in the fetal adrenal, although there is no direct proof of this. Studies of mice harboring Gata4 loss-of-function mutations suggest that this transcription factor is not required for the differentiation of fetal adrenocortical cells (88,154).

Consistent with its proposed role in the biosynthesis of adrenal androgens and other corticoids, GATA6 has been shown to act in synergy with SF-1 (NR5A1) and other factors to enhance the transcription of CYP11A1 (156), CYP17A1 (38), cytochrome b5 (CYB5) (159), hydroxysteroid sulfotransferase (SULT2A1) (156,160,161), and HSD3B2 (35) in cell lines (see Table 2 ​ 2). ). In the case of the CYP17A1 promoter, GATA6 does not act through a GATA response element but instead through interactions with another transcription factor, specificity protein 1 (SP1) (38). In the case of CYB5, GATA6 enhances promoter activity through interactions with specificity protein 3 (SP3) (159). GATA4 can substitute for GATA6 in transactivation studies of the CYP17A1 promoter (38), suggesting that GATA4 may serve to augment CYP17A1 expression during fetal development. In addition to normal adrenal cortex, GATA4 may regulate gene expression in disease states (described below).

The differentiation, growth, and survival of steroidogenic cells in the adrenal gland are controlled by a diverse array of hormones. Endocrine hormones and paracrine factors traditionally associated with the function of gonadal steroidogenic cells, such as LH, inhibins, and activins, also influence the differentiation, proliferation and function of adrenocortical cells, both in physiological and pathophysiological states. There is no direct evidence that GATA6 is hormonally regulated in the normal adrenal. Steady-state levels of Gata6 mRNA in the adrenal gland do not change markedly in mice treated with ACTH or dexamethasone (157), nor does there appear to be a diurnal variation in GATA6 expression in the adrenal. Administration of dibutyryl cAMP to NCI-H295A human adrenocortical cells has been shown to increase GATA6 mRNA levels, raising the possibility of hormonal regulation of GATA6 in the human adrenal cortex, but the physiological relevance of this finding in vivo remains to be established. GATA6 protein is down-regulated in response to mitogenic signals in some cell types (162,163), but there is no evidence supporting a role for GATA6 during proliferation in the adrenal cortex. Human chorionic gonadotropin up-regulates Gata4 and LH receptor (Lhcgr) expression in a dose-dependent manner (164). GATA4 has a role in the induced, but not basal, regulation of the LH receptor (Lhcgr) promoter in adrenocortical tumor cells. Ectopic expression of GATA4 in the adrenal heralds the appearance of neoplastic cells (164), and this factor may serve to integrate intracellular signals evoked by different hormones.

GATA FACTORS AND ENDOCRINE DISEASE

Gonadal Disorders and Tumorigenesis

To date, reports of gonadal disorders involving GATA4 or its associated cofactors have been scarce. Human mutations in the NR5A1 gene have been identified in individuals with 46,XY sex reversal with gonadal dysgenesis and adrenal insufficiency (165,166,167). Some of the cases involved retained Müllerian duct derivatives, indicating insufficient AMH production during fetal life. One of the heterozygous NR5A1 mutations (G35E) was found to act as a dominant-negative competitor of the synergism between GATA4 and the wild-type NR5A1 protein at the level of the AMH promoter (168). This suggested that proper GATA4/SF-1 is essential for normal AMH transcription in humans (168). Although not targeting the GATA4 gene itself, a recently described de novo t(8;10) chromosomal translocation associated with heart defects and hypergonadotropic hypogonadism has been linked to the gene encoding the GATA4 cofactor FOG2 (169). The resulting truncated FOG2 protein, however, did not appear to impair AMH expression because the patient had no signs of Müllerian duct retention. Thus, unlike the mouse (88), FOG2 might be dispensable for the initiation of testicular development in humans.

In vitro studies have suggested roles for GATA factors in the regulation of steroidogenesis in both gonadal and adrenal cells (104,156). Patients with polycystic ovary syndrome (PCOS) have hyperandrogenism of both ovarian and adrenal origin. The gene expression pattern as well as the response to hormonal stimulation of PCOS theca cells differs significantly from their normal counterparts (170,171). Interestingly, steady-state GATA6 mRNA levels are augmented in PCOS theca cells due to increased gene transcription and stability of the GATA6 transcripts (172). No sequence variations at the GATA6 locus, however, were associated with PCOS patients (172), suggesting that regulatory factors acting at the level of the GATA6 promoter might be differentially expressed in normal vs. PCOS theca cells.

Ovarian carcinomas account for up to 90% of ovarian cancer and typically have a poor prognosis related to a delay in detection. They originate from the surface epithelium and occur in various forms, the most common being serous carcinoma. The serous carcinomas commonly exhibit loss of heterozygosity (LOH) in the locus 8p21–23, which bears the GATA4 gene. In mucinous carcinomas, this LOH is less common (173). Of interest, GATA4 protein expression is lost in practically all serous carcinomas (516 of 528 samples studied) but in only some mucinous carcinomas (26 of 75 samples studied) (173). Moreover, in the mucinous carcinomas, the loss of GATA4 expression correlates inversely with the grade and clinical stage of the tumors (173). In general, LOH correlates with loss of GATA4 expression in the tumors, suggesting that loss of the other allele is enough to completely silence GATA4 expression. More recent findings indicate that the GATA4 gene is often silenced in ovarian carcinomas by histone modifications. In various ovarian cancer cell lines, GATA4 expression is usually negative due to methylation of its gene promoter (174,175). However, none of the analyzed serous carcinoma samples (n =7) exhibited a GATA4 methylated state (175), indicating that LOH is the only reason for the absence of GATA4 expression in the serous subtype. In one study, GATA4 was found to be expressed in most of the studied ovarian carcinomas of different subtypes (43 of 50 samples); in contrast to previous findings (173), 30 of these tumors were of serous type, and only six were GATA4 negative (176). Instead, the authors found a frequent loss of GATA6 protein correlated with a loss of several markers of normal epithelium such as disabled-2, collagen IV, and laminin (176). Taken together, loss of GATA4 and/or GATA6 expression, due to LOH or histone modifications, is likely involved in the dedifferentiation of the ovarian epithelium and ovarian carcinogenesis.

Granulosa cell tumors (GCTs) are rare, accounting for 3–5% of all ovarian cancers (176,177). They are steroidogenically active, typically causing precocious puberty, disturbances in menstrual cycle, and endometrial hyperplasia or cancer (176,177). Although poorly understood, the pathogenesis of GCTs involves defects in the regulation of granulosa cell proliferation (178). Recent findings suggest that GATA4 and GATA6 play a role in granulosa cell tumorigenesis (122). The majority of the analyzed 80 GCTs expressed GATA4 and GATA6 as well as NR5A1 and FOG2 protein at levels comparable with those in normal granulosa cells (122). However, negative or weak GATA6 protein expression is associated with a large tumor size, suggesting that GATA6 has a role in suppressing proliferation (122). This hypothesis is supported by findings in both glomerular and vascular smooth muscle cells, in which GATA6 is able to induce cell cycle arrest by activating and/or stabilizing p21 cip1 (Cdkn1a) expression (163,179).

Thus, GATA4 likely has an opposing role to GATA6 in granulosa cell tumorigenesis. GATA4 expression associates with aggressive behavior in a subgroup of GCTs, suggesting that it may facilitate proliferation and suppress apoptosis in granulosa cells (122). The vast majority of the analyzed GCTs expressed GATA4 at an intermediate or high level corresponding to its expression in normal granulosa cells (122). GATA4 expression associates with clinical stage (122); GATA4 expression is high in 60% of tumors spread outside the ovary (stage Ic and beyond). Furthermore, high GATA4 expression correlates with recurrence risk of the GCT patients, suggesting that GATA4 immunostaining may have value as a prognostic tool in human GCTs. The reasons for high GATA4 expression in aggressive GCTs, however, remain unknown and therefore need further study.

GCTs and adrenal tumors (described below) of both mice and humans exhibit similarities in their GATA expression patterns. Given the common embryonic origin of adrenocortical cells and ovarian granulosa cells, the GATA4/GATA6 ratio may serve as an essential element in the balanced regulation of proliferation vs. apoptosis. Potential target genes involved in these processes in the ovary include cyclin D2 (Ccnd2) and the antiapoptotic genes Bcl2 and Bcl2l1, which have been shown to be under GATA control in other organs (180,181,182). Cyclin D2 is essential for granulosa cell proliferation and plays a role in GCT development (183,184). Our unpublished results show that GATA4 expression is associated with CCND2 and BCL2 expression in GCTs and that the proximal promoters of both genes are activated by GATA4 in granulosa tumor cells.

Adrenal Disorders and Tumorigenesis

Although not normally expressed in the postnatal adrenal cortex, ectopic GATA4 production has been linked to disease states in this tissue (e.g. adrenocortical tumors; see below). Given their expression patterns and target genes, it is reasonable to postulate that GATA factors may be relevant to adrenal insufficiency or other diseases characterized by aberrant steroidogenic gene expression alone or together with other factors. For example, a de novo heterozygous mutation (G35E) in the NR5A1 gene has been shown to be responsible for adrenal insufficiency and pseudohermaphroditism (185). This mutant specifically fails to synergize with GATA factors on the HSD3B2 promoter (35). GATA6 immunoreactivity is significantly diminished in most human adrenocortical adenomas and carcinomas (157,186). This decrease in GATA6 expression may be an important event for the escape of tumor cells from normal control mechanisms, although there is no direct proof of this premise. Consistent with its proposed role in adrenal androgen biosynthesis in the zona reticularis, GATA6 expression is retained in a significant fraction of virilizing adrenocortical tumors, especially carcinomas (187,188). GATA4 mRNA is expressed in only a small proportion of human adenomas and carcinomas (157,187,188). Larger amounts of GATA4 mRNA have been found among those presenting aggressive clinical behavior, although its value as a prognostic marker remains to be established (189).

Gonadectomy causes cells in the mouse adrenal cortex to transform into sex steroid-producing cells that are histologically and functionally similar to gonadal tissue (190). This phenomenon is strain dependent; susceptible strains include CE, DBA/2J, and NU/J. When these mice are gonadectomized, small, basophilic cells, known as A cells, accumulate in the subcapsular region of the adrenal cortex (191). Type A cells express GATA4 and AMH type 2 receptor (AMHR2) but lack expression of steroidogenic markers (164,192). Functionally, A cells resemble stromal cells of the postmenopausal ovary, which can metabolize cholesterol into oxysterols but have limited capacity for the synthesis of sex steroids (193). Later, foci of large, sex steroid-producing cells, termed B cells, appear in the adrenal cortex (194). B cells express Gata4, Nr5a1, Lhcgr, Inha, Amh, estrogen receptor α (Esr1), Cyp17a1, and an ovary-specific alternative splice variant of Cyp19a1 (164,192). Type B cells resemble follicular theca cells from women with PCOS, a condition marked by chronically elevated LH levels (195). Traditional adrenocortical cell markers, such as the melanocortin 2 receptor (MC2R) or enzymes for the synthesis of corticosterone or aldosterone [e.g. steroid 21-hydroxylase (Cyp21a1), P450 11β-hydroxylase (Cyp11b1), and aldosterone synthase (Cyp11b2)] are not expressed in A or B cells (164). Given that many of the genes expressed in A and B cells, such as Lhcgr, Inha, Amh, and Cyp17a1, harbor GATA-binding sites in their promoters, increased GATA4 levels may be postulated to lead to their enhanced expression in these cells.

When Inha promoter-SV40 T-antigen transgenic mice are subject to prepubertal gonadectomy, they develop sex steroid-producing adrenocortical carcinomas by 5–7 months of age (196,197). These adrenocortical carcinomas generally arise in the X-zone, but subcapsular pates of type A and B cells can accompany the X-zone lesions. The molecular markers of adrenocortical neoplasia in these mice, Lhcgr, Inha, Gata4, and Cyp17a1, are similar to those described in gonadectomized DBA/2J mice. GATA6 is also down-regulated during adrenocortical tumorigenesis in these transgenic mice. The phenomenon of gonadectomy-induced adrenocortical neoplasia has also been observed in other small animals, including rats, guinea pigs, hamsters, and ferrets (198). In the ferret adrenal, GATA4 immunoreactivity can be seen in both small and large neoplastic cells and seems to correlate with the degree of nuclear and cytoplasmic atypia (199). GATA4 is particularly abundant in anaplastic myxoid adrenocortical carcinomas but is absent from the spindle cell component of adrenocortical tumors (199). Thus, taken together, it seems likely that GATA4 serves an essential function in gonadectomy-induced adrenocortical tumorigenesis, given its established role in differentiation of gonadal stroma (88).

SUMMARY

Over the past decade, it has become plainly evident that the critical nature of GATA regulatory proteins is not simply a matter of the cardiac and hematopoietic systems. Indeed, the abundant expression of GATA proteins in multiple cell types of various endocrine organs along with their ever-expanding list of target genes is a strong indication that these factors are essential regulators of cell-specific gene expression required for the development, differentiation, and function of endocrine cells. One must be wary, however, that most studies to date have relied heavily on in vitro transactivation assays, DNA-binding analyses, and to a lesser extent chromatin immunoprecipitation. Although steadily increasing, the number of reports relying on genetics and other in vivo models remain limited as are cases of human endocrine-related disorders associated with GATA mutations and/or deregulated GATA function. Although several studies have implicated GATA factors in endocrine tumors, the underlying mechanisms remain to be elucidated. The future challenge is then to continue applying genetic models to validate the bulk of in vitro data that is currently available. For some endocrine organs, this appears to be a somewhat daunting task. This is particularly true of the gonads and adrenal where the overlapping expression of different GATA proteins in various cell types (see Fig. 2 ​ 2) ) and the potential for compensatory mechanisms render individual Gata gene knockout approaches in mice difficult to interpret. A case in point is the Sertoli cell-specific knockout of the Gata1 gene in the adult testis, which produced no overt testicular phenotype (87). In these particular cases, more sophisticated approaches will undoubtedly be required.

Acknowledgments

Drs. Jorma Toppari (University of Turku, Finland) and Timo Otonkoski (University of Helsinki, Finland) are thanked for critical reading of the manuscript.

Footnotes

This work was supported in part by a grant from the Canadian Institutes of Health Research (CIHR) to R.S.V. and by a grant from the Sigrid Juselius Foundation to M.H. and M.A. R.S.V. is titleholder of the Canada Research Chair in Reproduction and Sex Development. S.M.G. was a recipient of a postdoctoral fellowship from the CIHR Institute of Gender and Health. D.B.W. is supported by National Institutes of Health Grant DK075618.

Disclosure Statement: The authors have nothing to disclose.

First Published Online January 3, 2008

Abbreviations: AMH, Anti-Müllerian hormone; CBP, CREB-binding protein; CRE, cAMP response element; CREB, CRE-binding protein; e13.5, embryonic d 13.5; FOG, Friend of GATA; GCT, granulosa cell tumor; GLP1, GATA-like protein 1; αGSU, α-glycoprotein subunit; LOH, loss of heterozygosity; PCOS, polycystic ovary syndrome; PKA, protein kinase A; SF-1, steroidogenic factor 1.

References

• Weiss MJ, Orkin SH 1995 GATA transcription factors: key regulators of hematopoiesis. Exp Hematol 23:99–107 [PubMed] [Google Scholar]
• George KM, Leonard MW, Roth ME, Lieuw KH, Kioussis D, Grosveld F, Engel JD 1997 Embryonic expression and cloning of the murine GATA-3 gene. Development 120:2673–2686 [PubMed] [Google Scholar]
• Nardelli J, Thiesson D, Fujiwara Y, Tsai FY, Orkin SH 1999 Expression and genetic interaction of transcription factors GATA-2 and GATA-3 during development of the mouse central nervous system. Dev Biol 210:305–321 [PubMed] [Google Scholar]
• Lillevali K, Matilainen T, Karis A, Salminen M 2004 Partially overlapping expression of Gata2 and Gata3 during inner ear development. Dev Dyn 231:775–781 [PubMed] [Google Scholar]
• Molkentin JD 2000 The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem 275:38949–38952 [PubMed] [Google Scholar]
• Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C, Leiden JM 1997 GATA-4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11:1048–1060 [PubMed] [Google Scholar]
• Molkentin JD, Lin Q, Duncan SA, Olson EN 1997 Requirement of the transcription factor GATA-4 for heart tube formation and ventral morphogenesis. Genes Dev 11:1061–1072 [PubMed] [Google Scholar]
• Morrisey EE, Tang Z, Sigrist K, Lu MM, Jiang F, Ip HS, Parmacek MS 1998 GATA-6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev 12:3579–3590 [PMC free article] [PubMed] [Google Scholar]
• Koutsourakis M, Langeveld A, Patient R, Beddington R, Grosveld F 1999 The transcription factor GATA-6 is essential for early extraembryonic development. Development 126:723–732 [PubMed] [Google Scholar]
• Molkentin JD, Tymitz KM, Richardson JA, Olson EN 2000 Abnormalities of the genitourinary tract in female mice lacking GATA-5. Mol Cell Biol 20:5256–5260 [PMC free article] [PubMed] [Google Scholar]
• Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D 2003 GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447 [PubMed] [Google Scholar]
• Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM, Weiss MJ 2000 Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet 24:266–270 [PMC free article] [PubMed] [Google Scholar]
• Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Hardling B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker R, Devriendt K 2000 GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406:419–422 [PubMed] [Google Scholar]
• Ko LJ, Engel JD 1993 DNA-binding specificities of the GATA transcription factor family. Mol Cell Biol 13:4011–4022 [PMC free article] [PubMed] [Google Scholar]
• Merika M, Orkin SH 1993 DNA-binding specificity of GATA family transcription factors. Mol Cell Biol 13:3999–4010 [PMC free article] [PubMed] [Google Scholar]
• Pandolfi PP, Roth ME, Karis A, Leonard MW, Dzierzak E, Grosveld FG, Engel JD, Lindenbaum MH 1995 Targeted disruption of the GATA-3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat Genet 11:40–44 [PubMed] [Google Scholar]
• Pevny L, Simon MC, Robertson E, Klein WH, Tsai SF, D'Agati V, Orkin SH, Costantini F 1991 Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349:257–260 [PubMed] [Google Scholar]
• Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, Alt FW, Orkin SH 1994 An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371:221–226 [PubMed] [Google Scholar]
• Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M 1997 The cardiac transcription factors Nkx-2.5 and GATA-4 are mutual cofactors. EMBO J 16:5687–5696 [PMC free article] [PubMed] [Google Scholar]
• Lee Y, Shioi T, Kasahara H, Jobe SM, Wiese RJ, Markham BE, Izumo S 1998 The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Mol Cell Biol 18:3120–3129 [PMC free article] [PubMed] [Google Scholar]
• Gordon DF, Lewis SR, Haugen BR, James RA, McDermott MT, Wood WM, Ridgway EC 1997 Pit-1 and GATA-2 interact and functionally cooperate to activate the thyrotropin β-subunit promoter. J Biol Chem 272:24339–24347 [PubMed] [Google Scholar]
• Gregory RC, Taxman DJ, Seshasayee D, Kensinger MH, Bieker JJ, Wojchowski DM 1996 Functional interaction of GATA1 with erythroid Kruppel-like factor and Sp1 at defined erythroid promoters. Blood 87:1793–1801 [PubMed] [Google Scholar]
• Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH 1995 Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. Proc Natl Acad Sci USA 92:9585–9589 [PMC free article] [PubMed] [Google Scholar]
• Ono Y, Fukuhara N, Yoshie O 1998 TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3. Mol Cell Biol 18:6939–6950 [PMC free article] [PubMed] [Google Scholar]
• Tevosian SG, Deconinck AE, Cantor AB, Rieff HI, Fujiwara Y, Corfas G, Orkin SH 1999 FOG-2: a novel GATA-family cofactor related to multitype zinc-finger proteins Friend of GATA-1 and U-shaped. Proc Natl Acad Sci USA 96:950–955 [PMC free article] [PubMed] [Google Scholar]
• Lu JR, McKinsey A, Xu H, Wang DZ, Richardson JA, Olson EN 1999 FOG-2, a heart- and brain-enriched cofactor for GATA transcription factors. Mol Cell Biol 19:4495–4502 [PMC free article] [PubMed] [Google Scholar]
• Tremblay JJ, Viger RS 1999 Transcription factor GATA-4 enhances Müllerian inhibiting substance gene transcription through a direct interaction with the nuclear receptor SF-1. Mol Endocrinol 13:1388–1401 [PubMed] [Google Scholar]
• Svensson EC, Tufts RL, Polk CE, Leiden JM 1999 Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes. Proc Natl Acad Sci USA 96:956–961 [PMC free article] [PubMed] [Google Scholar]
• Nerlov C, Querfurth E, Kulessa H, Graf T 2000 GATA-1 interacts with the myeloid PU. 1 transcription factor and represses PU.1-dependent transcription. Blood 95:2543–2551 [PubMed] [Google Scholar]
• Rekhtman N, Radparvar F, Evans T, Skoultchi AI 1999 Direct interaction of hematopoietic transcription factors PU.1 and GATA- 1: functional antagonism in erythroid cells. Genes Dev 13:1398–1411 [PMC free article] [PubMed] [Google Scholar]
• Morin S, Charron F, Robitaille L, Nemer M 2000 GATA-dependent recruitment of MEF2 proteins to target promoters. EMBO J 19:2046–2055 [PMC free article] [PubMed] [Google Scholar]
• Kawana M, Lee ME, Quertermous EE, Quertermous T 1995 Cooperative interaction of GATA-2 and AP1 regulates transcription of the endothelin-1 gene. Mol Cell Biol 15:4225–4231 [PMC free article] [PubMed] [Google Scholar]
• Dai YS, Markham BE 2001 p300 Functions as a coactivator of transcription factor GATA-4. J Biol Chem 276:37178–37185 [PubMed] [Google Scholar]
• Tremblay JJ, Hamel F, Viger RS 2002 Protein kinase A-dependent cooperation between GATA and C/EBP transcription factors regulates StAR promoter activity. Endocrinology 143:3935–3945 [PubMed] [Google Scholar]
• Martin LJ, Taniguchi H, Robert NM, Simard J, Tremblay JJ, Viger RS 2005 GATA factors and the nuclear receptors, steroidogenic factor 1/liver receptor homolog 1, are key mutual partners in the regulation of the human 3β-hydroxysteroid dehydrogenase type 2 promoter. Mol Endocrinol 19:2358–2370 [PubMed] [Google Scholar]
• Robert NM, Miyamoto Y, Taniguchi H, Viger RS 2006 LRH-1/NR5A2 cooperates with GATA factors to regulate inhibin α-subunit promoter activity. Mol Cell Endocrinol 257–258:65–74 [PubMed] [Google Scholar]
• Stennard FA, Costa MW, Elliott DA, Rankin S, Haast SJ, Lai D, McDonald LP, Niederreither K, Dolle P, Bruneau BG, Zorn AM, Harvey RP 2003 Cardiac T-box factor Tbx20 directly interacts with Nkx2–5, GATA4, and GATA5 in regulation of gene expression in the developing heart. Dev Biol 262:206–224 [PubMed] [Google Scholar]
• Flück CE, Miller WL 2004 GATA-4 and GATA-6 modulate tissue-specific transcription of the human gene for P450c17 by direct interaction with Sp1. Mol Endocrinol 18:1144–1157 [PubMed] [Google Scholar]
• Eisbacher M, Holmes ML, Newton A, Hogg PJ, Khachigian LM, Crossley M, Chong BH 2003 Protein-protein interaction between Fli-1 and GATA-1 mediates synergistic expression of megakaryocyte-specific genes through cooperative DNA binding. Mol Cell Biol 23:3427–3441 [PMC free article] [PubMed] [Google Scholar]
• Du J, Stankiewicz MJ, Liu Y, Xi Q, Schmitz JE, Lekstrom-Himes JA, Ackerman SJ 2002 Novel combinatorial interactions of GATA-1, PU.1, and C/EBPε isoforms regulate transcription of the gene encoding eosinophil granule major basic protein. J Biol Chem 277:43481–43494 [PubMed] [Google Scholar]
• Dai YS, Cserjesi P, Markham BE, Molkentin JD 2002 The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism. J Biol Chem 277:24390–24398 [PubMed] [Google Scholar]
• Krasinski SD, Van Wering HM, Tannemaat MR, Grand RJ 2001 Differential activation of intestinal gene promoters: functional interactions between GATA-5 and HNF-1α. Am J Physiol Gastrointest Liver Physiol 281:G69–G84 [PubMed] [Google Scholar]
• McNagny KM, Sieweke MH, Doderlein G, Graf T, Nerlov C 1998 Regulation of eosinophil-specific gene expression by a C/EBP-Ets complex and GATA-1. EMBO J 17:3669–3680 [PMC free article] [PubMed] [Google Scholar]
• Zhang Y, Rath N, Hannenhalli S, Wang Z, Cappola T, Kimura S, tochina-Vasserman E, Lu MM, Beers MF, Morrisey EE 2007 GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo. Development 134:189–198 [PubMed] [Google Scholar]
• Mao C, Tai WC, Bai Y, Poizat C, Lee AS 2006 In vivo regulation of Grp78/BiP transcription in the embryonic heart: role of the endoplasmic reticulum stress response element and GATA-4. J Biol Chem 281:8877–8887 [PubMed] [Google Scholar]
• Lawson MA, Mellon PL 1998 Expression of GATA-4 in migrating gonadotropin-releasing neurons of the developing mouse. Mol Cell Endocrinol 140:157–161 [PubMed] [Google Scholar]
• Dasen JS, O'Connell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, Hooshmand F, Aggarwal AK, Rosenfeld MG 1999 Reciprocal interactions of Pit1 and GATA-2 mediate signaling gradient-induced determination of pituitary cell types. Cell 97:587–598 [PubMed] [Google Scholar]
• Steger DJ, Hecht JH, Mellon PL 1994 GATA-binding proteins regulate the human gonadotropin α-subunit gene in the placenta and pituitary gland. Mol Cell Biol 14:5592–5602 [PMC free article] [PubMed] [Google Scholar]
• Gordon DF, Woodmansee WW, Black JN, Dowding JM, drick-Peart J, Wood WM, Ridgway EC 2002 Domains of Pit-1 required for transcriptional synergy with GATA-2 on the TSHβ gene. Mol Cell Endocrinol 196:53–66 [PubMed] [Google Scholar]
• Pincas H, Amoyel K, Counis R, Laverriere JN 2001 Proximal cis-acting elements, including steroidogenic factor 1, mediate the efficiency of a distal enhancer in the promoter of the rat gonadotropin-releasing hormone receptor gene. Mol Endocrinol 15:319–337 [PubMed] [Google Scholar]
• Scully KM, Rosenfeld MG 2002 Pituitary development: regulatory codes in mammalian organogenesis. Science 295:2231–2235 [PubMed] [Google Scholar]
• Charles MA, Saunders TL, Wood WM, Owens K, Parlow AF, Camper SA, Ridgway EC, Gordon DF 2006 Pituitary-specific Gata2 knockout: effects on gonadotrope and thyrotrope function. Mol Endocrinol 20:1366–1377 [PubMed] [Google Scholar]
• Umeoka K, Sanno N, Osamura RY, Teramoto A 2002 Expression of GATA-2 in human pituitary adenomas. Mod Pathol 15:11–17 [PubMed] [Google Scholar]
• Hilfer SR, Brown JW 1984 The development of pharyngeal endocrine organs in mouse and chick embryos. Scan Electron Microsc 2009–2022 [PubMed] [Google Scholar]
• Debacker C, Catala M, Labastie MC 1999 Embryonic expression of the human GATA-3 gene. Mech Dev 85:183–187 [PubMed] [Google Scholar]
• He B, Tong TK, Hiou-Tim FF, Al-Akad B, Kronenberg HM, Karaplis AC 2002 The murine gene encoding parathyroid hormone: genomic organization, nucleotide sequence and transcriptional regulation. J Mol Endocrinol 29:193–203 [PubMed] [Google Scholar]
• Lim KC, Lakshmanan G, Crawford SE, Gu Y, Grosveld F, Engel JD 2000 Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system. Nat Genet 25:209–212 [PubMed] [Google Scholar]
• Nesbit MA, Bowl MR, Harding B, Ali A, Ayala A, Crowe C, Dobbie A, Hampson G, Holdaway I, Levine MA, McWilliams R, Rigden S, Sampson J, Williams AJ, Thakker RV 2004 Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. J Biol Chem 279:22624–22634 [PubMed] [Google Scholar]
• Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, Yamamoto K, Fujimoto S, Seishu S, Fukushima Y, Hasegawa Y, Ogata T 2001 GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 38:374–380 [PMC free article] [PubMed] [Google Scholar]
• Zahirieh A, Nesbit MA, Ali A, Wang K, He N, Stangou M, Bamichas G, Sombolos K, Thakker RV, Pei Y 2005 Functional analysis of a novel GATA3 mutation in a family with the hypoparathyroidism, deafness, and renal dysplasia syndrome. J Clin Endocrinol Metab 90:2445–2450 [PubMed] [Google Scholar]
• Mino Y, Kuwahara T, Mannami T, Shioji K, Ono K, Iwai N 2005 Identification of a novel insertion mutation in GATA3 with HDR syndrome. Clin Exp Nephrol 9:58–61 [PubMed] [Google Scholar]
• Adachi M, Tachibana K, Asakura Y, Tsuchiya T 2006 A novel mutation in the GATA3 gene in a family with HDR syndrome (hypoparathyroidism, sensorineural deafness and renal anomaly syndrome). J Pediatr Endocrinol Metab 19:87–92 [PubMed] [Google Scholar]
• Chiu WY, Chen HW, Chao HW, Yann LT, Tsai KS 2006 Identification of three novel mutations in the GATA3 gene responsible for familial hypoparathyroidism and deafness in the Chinese population. J Clin Endocrinol Metab 91:4587–4592 [PubMed] [Google Scholar]
• Searcy RD, Vincent EB, Liberatore CM, Yutzey KE 1998 A GATA-dependent nkx-2.5 regulatory element activates early cardiac gene expression in transgenic mice. Development 125:4461–4470 [PubMed] [Google Scholar]
• Shaw-White JR, Bruno MD, Whitsett JA 1999 GATA-6 activates transcription of thyroid transcription factor-1. J Biol Chem 274:2658–2664 [PubMed] [Google Scholar]
• Jensen J, Heller RS, Funder-Nielsen T, Pedersen EE, Lindsell C, Weinmaster G, Madsen OD, Serup P 2000 Independent development of pancreatic α- and β-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes 49:163–176 [PubMed] [Google Scholar]
• McKinnon CM, Docherty K 2001 Pancreatic duodenal homeobox-1, PDX-1, a major regulator of β-cell identity and function. Diabetologia 44:1203–1214 [PubMed] [Google Scholar]
• Decker K, Goldman DC, Grasch CL, Sussel L 2006 Gata6 is an important regulator of mouse pancreas development. Dev Biol 298:415–429 [PMC free article] [PubMed] [Google Scholar]
• Ketola I, Otonkoski T, Pulkkinen MA, Niemi H, Palgi J, Jacobsen CM, Wilson DB, Heikinheimo M 2004 Transcription factor GATA-6 is expressed in the endocrine and GATA-4 in the exocrine pancreas. Mol Cell Endocrinol 226:51–57 [PubMed] [Google Scholar]
• Ritz-Laser B, Mamin A, Brun T, Avril I, Schwitzgebel VM, Philippe J 2005 The zinc finger-containing transcription factor Gata-4 is expressed in the developing endocrine pancreas and activates glucagon gene expression. Mol Endocrinol 19:759–770 [PubMed] [Google Scholar]
• Watt AJ, Zhao R, Li J, Duncan SA 2007 Development of the mammalian liver and ventral pancreas is dependent on GATA4. BMC Dev Biol 7:37 [PMC free article] [PubMed] [Google Scholar]
• Fu B, Guo M, Wang S, Campagna D, Luo M, Herman JG, Iacobuzio-Donahue CA 2007 Evaluation of GATA-4 and GATA-5 methylation profiles in human pancreatic cancers indicate promoter methylation patterns distinct from other human tumor types. Cancer Biol Ther 6:1546–1552 [PubMed] [Google Scholar]
• LaVoie HA 2003 The role of GATA in mammalian reproduction. Exp Biol Med 228:1282–1290 [PubMed] [Google Scholar]
• Viger RS, Taniguchi H, Robert NM, Tremblay JJ 2004 Role of the GATA family of transcription factors in andrology. J Androl 25:441–452 [PubMed] [Google Scholar]
• Siggers P, Smith L, Greenfield A 2002 Sexually dimorphic expression of Gata-2 during mouse gonad development. Mech Dev 111:159–162 [PubMed] [Google Scholar]
• Anttonen M, Ketola I, Parviainen H, Pusa AK, Heikinheimo M 2003 FOG-2 and GATA-4 are coexpressed in the mouse ovary and can modulate Mullerian-inhibiting substance expression. Biol Reprod 68:1333–1340 [PubMed] [Google Scholar]
• Imai T, Kawai Y, Tadokoro Y, Yamamoto M, Nishimune Y, Yomogida K 2004 In vivo and in vitro constant expression of GATA-4 in mouse postnatal Sertoli cells. Mol Cell Endocrinol 214:107–115 [PubMed] [Google Scholar]
• Ketola I, Rahman N, Toppari J, Bielinska M, Porter-Tinge SB, Tapanainen JS, Huhtaniemi IT, Wilson DB, Heikinheimo M 1999 Expression and regulation of transcription factors GATA-4 and GATA-6 in developing mouse testis. Endocrinology 140:1470–1480 [PubMed] [Google Scholar]
• Ketola I, Anttonen M, Vaskivuo T, Tapanainen JS, Toppari J, Heikinheimo M 2002 Developmental expression and spermatogenic stage specificity of transcription factors GATA-1 and GATA-4 and their cofactors FOG-1 and FOG-2 in the mouse testis. Eur J Endocrinol 147:397–406 [PubMed] [Google Scholar]
• LaVoie HA, McCoy GL, Blake CA 2004 Expression of the GATA-4 and GATA-6 transcription factors in the fetal rat gonad and in the ovary during postnatal development and pregnancy. Mol Cell Endocrinol 227:31–40 [PubMed] [Google Scholar]
• McCoard SA, Wise TH, Fahrenkrug SC, Ford JJ 2001 Temporal and spatial localization patterns of GATA-4 during porcine gonadogenesis. Biol Reprod 65:366–374 [PubMed] [Google Scholar]
• Oreal E, Mazaud S, Picard JY, Magre S, Carre-Eusebe D 2002 Different patterns of anti-Mullerian hormone expression, as related to DMRT1, SF-1, WT1, GATA-4, Wnt-4, and Lhx9 expression, in the chick differentiating gonads. Dev Dyn 225:221–232 [PubMed] [Google Scholar]
• Viger RS, Mertineit C, Trasler JM, Nemer M 1998 Transcription factor GATA-4 is expressed in a sexually dimorphic pattern during mouse gonadal development and is a potent activator of the Müllerian inhibiting substance promoter. Development 125:2665–2675 [PubMed] [Google Scholar]
• Ketola I, Toppari J, Vaskivuo T, Herva R, Tapanainen JS, Heikinheimo M 2003 Transcription factor GATA-6, cell proliferation, apoptosis, and apoptosis-related proteins Bcl-2 and Bax in human fetal testis. J Clin Endocrinol Metab 88:1858–1865 [PubMed] [Google Scholar]
• Yomogida K, Ohtani H, Harigae H, Ito E, Nishimune Y, Engel JD, Yamamoto M 1994 Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells. Development 120:1759–1766 [PubMed] [Google Scholar]
• Ketola I, Pentikainen V, Vaskivuo T, Ilvesmaki V, Herva R, Dunkel L, Tapanainen JS, Toppari J, Heikinheimo M 2000 Expression of transcription factor GATA-4 during human testicular development and disease. J Clin Endocrinol Metab 85:3925–3931 [PubMed] [Google Scholar]
• Lindeboom F, Gillemans N, Karis A, Jaegle M, Meijer D, Grosveld F, Philipsen S 2003 A tissue-specific knockout reveals that Gata1 is not essential for Sertoli cell function in the mouse. Nucleic Acids Res 31:5405–5412 [PMC free article] [PubMed] [Google Scholar]
• Tevosian SG, Albrecht KH, Crispino JD, Fujiwara Y, Eicher EM, Orkin SH 2002 Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development 129:4627–4634 [PubMed] [Google Scholar]
• Manuylov NL, Fujiwara Y, Adameyko II, Poulat F, Tevosian SG 2007 The regulation of Sox9 gene expression by the GATA4/FOG2 transcriptional complex in dominant XX sex reversal mouse models. Dev Biol 307:356–367 [PMC free article] [PubMed] [Google Scholar]
• Bouma GJ, Washburn LL, Albrecht KH, Eicher EM 2007 Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice. Proc Natl Acad Sci USA 104:14994–14999 [PMC free article] [PubMed] [Google Scholar]
• Bielinska M, Seehra A, Toppari J, Heikinheimo M, Wilson DB 2007 GATA-4 is required for sex steroidogenic cell development in the fetal mouse. Dev Dyn 236:203–213 [PMC free article] [PubMed] [Google Scholar]
• Li S, Lu MM, Zhou D, Hammes SR, Morrisey EE 2007 GLP-1: a novel zinc finger protein required in somatic cells of the gonad for germ cell development. Dev Biol 301:106–116 [PMC free article] [PubMed] [Google Scholar]
• Sze KL, Lee WM, Lui WY 2008 Expression of CLMP, a novel tight junction protein, is mediated via the interaction of GATA with the kruppel family proteins, KLF4 and Sp1, in mouse TM4 Sertoli cells. J Cell Physiol 214:334–344 [PubMed] [Google Scholar]
• Lui WY, Wong EW, Guan Y, Lee WM 2007 Dual transcriptional control of claudin-11 via an overlapping GATA/NF-Y motif: positive regulation through the interaction of GATA, NF-YA, and CREB and negative regulation through the interaction of Smad, HDAC1, and mSin3A. J Cell Physiol 211:638–648 [PubMed] [Google Scholar]
• Florin A, Maire M, Bozec A, Hellani A, Chater S, Bars R, Chuzel F, Benahmed M 2005 Androgens and postmeiotic germ cells regulate claudin-11 expression in rat Sertoli cells. Endocrinology 146:1532–1540 [PubMed] [Google Scholar]
• Denolet E, De GK, Allemeersch J, Engelen K, Marchal K, Van HP, Tan KA, Sharpe RM, Saunders PT, Swinnen JV, Verhoeven G 2006 The effect of a Sertoli cell-selective knockout of the androgen receptor on testicular gene expression in prepubertal mice. Mol Endocrinol 20:321–334 [PubMed] [Google Scholar]
• Wakabayashi J, Yomogida K, Nakajima O, Yoh K, Takahashi S, Engel JD, Ohneda K, Yamamoto M 2003 GATA-1 testis activation region is essential for Sertoli cell-specific expression of GATA-1 gene in transgenic mouse. Genes Cells 8:619–630 [PubMed] [Google Scholar]
• Onodera K, Yomogida K, Suwabe N, Takahashi S, Muraosa Y, Hayashi N, Ito E, Gu L, Rassoulzadegan M, Engel JD, Yamamoto M 1997 Conserved structure, regulatory elements, and transcriptional regulation from the GATA-1 gene testis promoter. J Biochem 121:251–263 [PubMed] [Google Scholar]
• Ito E, Toki T, Ishihara H, Ohtani H, Gu L, Yokoyama M, Engel JD, Yamamoto M 1993 Erythroid transcription factor GATA-1 is abundantly transcribed in mouse testis. Nature 362:466–468 [PubMed] [Google Scholar]
• Zhang Z, Wu AZ, Feng ZM, Mruk D, Cheng CY, Chen CL 2002 Gonadotropins, via cAMP, negatively regulate GATA-1 gene expression in testicular cells. Endocrinology 143:829–836 [PubMed] [Google Scholar]
• Heikinheimo M, Ermolaeva M, Bielinska M, Rahnman NA, Narita N, Huhtaniemi IT, Tapanainen JS, Wilson DB 1997 Expression and hormonal regulation of transcription factors GATA-4 and GATA-6 in the mouse ovary. Endocrinology 138:3505–3514 [PubMed] [Google Scholar]
• Mazaud Guittot S, Tetu A, Legault E, Pilon N, Silversides DW, Viger RS 2007 The proximal Gata4 promoter directs reporter gene expression to sertoli cells during mouse gonadal development. Biol Reprod 76:85–95 [PubMed] [Google Scholar]
• Ohara Y, Atarashi T, Ishibashi T, Ohashi-Kobayashi A, Maeda M 2006 GATA-4 gene organization and analysis of its promoter. Biol Pharm Bull 29:410–419 [PubMed] [Google Scholar]
• Tremblay JJ, Viger RS 2003 Novel roles for GATA transcription factors in the regulation of steroidogenesis. J Steroid Biochem Mol Biol 85:291–298 [PubMed] [Google Scholar]
• Tremblay JJ, Viger RS 2001 GATA factors differentially activate multiple gonadal promoters through conserved GATA regulatory elements. Endocrinology 142:977–986 [PubMed] [Google Scholar]
• Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ, Crossley M, Orkin SH 1997 FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 90:109–119 [PubMed] [Google Scholar]
• Fox AH, Liew C, Holmes M, Kowalski K, Mackay J, Crossley M 1999 Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers. EMBO J 18:2812–2822 [PMC free article] [PubMed] [Google Scholar]
• Holmes M, Turner J, Fox A, Chisholm O, Crossley M, Chong B 1999 hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation. J Biol Chem 274:23491–23498 [PubMed] [Google Scholar]
• Svensson EC, Huggins GS, Dardik FB, Polk CE, Leiden JM 2000 A functionally conserved N-terminal domain of the friend of GATA-2 (FOG-2) protein represses GATA4-dependent transcription. J Biol Chem 275:20762–20769 [PubMed] [Google Scholar]
• Robert NM, Tremblay JJ, Viger RS 2002 FOG-1 and FOG-2 differentially repress the GATA-dependent activity of multiple gonadal promoters. Endocrinology 143:3963–3973 [PubMed] [Google Scholar]
• Kitta K, Day RM, Kim Y, Torregroza I, Evans T, Suzuki YJ 2003 Hepatocyte growth factor induces GATA-4 phosphorylation and cell survival in cardiac muscle cells. J Biol Chem 278:4705–4712 [PubMed] [Google Scholar]
• Liang Q, Wiese RJ, Bueno OF, Dai YS, Markham BE, Molkentin JD 2001 The transcription factor GATA-4 is activated by extracellular signal- regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol Cell Biol 21:7460–7469 [PMC free article] [PubMed] [Google Scholar]
• Morimoto T, Hasegawa K, Kaburagi S, Kakita T, Wada H, Yanazume T, Sasayama S 2000 Phosphorylation of GATA-4 is involved in α1-adrenergic agonist-responsive transcription of the endothelin-1 gene in cardiac myocytes. J Biol Chem 275:13721–13726 [PubMed] [Google Scholar]
• Tremblay JJ, Viger RS 2003 Transcription factor GATA-4 is activated by phosphorylation of serine 261 via the cAMP/PKA pathway in gonadal cells. J Biol Chem 278:22128–22135 [PubMed] [Google Scholar]
• Yanazume T, Hasegawa K, Wada H, Morimoto T, Abe M, Kawamura T, Sasayama S 2002 Rho/ROCK pathway contributes to the activation of extracellular signal- regulated kinase/GATA-4 during myocardial cell hypertrophy. J Biol Chem 277:8618–8625 [PubMed] [Google Scholar]
• Wang J, Paradis P, Aries A, Komati H, Lefebvre C, Wang H, Nemer M 2005 Convergence of protein kinase C and JAK-STAT signaling on transcription factor GATA-4. Mol Cell Biol 25:9829–9844 [PMC free article] [PubMed] [Google Scholar]
• Tenhunen O, Sarman B, Kerkela R, Szokodi I, Papp L, Toth M, Ruskoaho H 2004 Mitogen-activated protein kinases p38 and ERK 1/2 mediate the wall stress-induced activation of GATA-4 binding in adult heart. J Biol Chem 279:24852–24860 [PubMed] [Google Scholar]
• Charron F, Tsimiklis G, Arcand M, Robitaille L, Liang Q, Molkentin JD, Meloche S, Nemer M 2001 Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA. Genes Dev 15:2702–2719 [PMC free article] [PubMed] [Google Scholar]
• LaVoie HA, Singh D, Hui YY 2004 Concerted regulation of the porcine StAR gene promoter activity by FSH and IGF-I in granulosa cells involves GATA-4 and C/EBPβ. Endocrinology 145:3122–3134 [PubMed] [Google Scholar]
• Kwintkiewicz J, Cai Z, Stocco C 2007 Follicle-stimulating hormone-induced activation of Gata4 contributes in the up-regulation of Cyp19 expression in rat granulosa cells. Mol Endocrinol 21:933–947 [PubMed] [Google Scholar]
• Vaskivuo TE, Anttonen M, Herva R, Billig H, Dorland M, te Velde ER, Stenback F, Heikinheimo M, Tapanainen JS 2001 Survival of human ovarian follicles from fetal to adult life: apoptosis, apoptosis-related proteins, and transcription factor GATA-4. J Clin Endocrinol Metab 86:3421–3429 [PubMed] [Google Scholar]
• Anttonen M, Unkila-Kallio L, Leminen A, Butzow R, Heikinheimo M 2005 High GATA-4 expression associates with aggressive behavior, whereas low anti-Mullerian hormone expression associates with growth potential of ovarian granulosa cell tumors. J Clin Endocrinol Metab 90:6529–6535 [PubMed] [Google Scholar]
• Laitinen MP, Anttonen M, Ketola I, Wilson DB, Ritvos O, Butzow R, Heikinheimo M 2000 Transcription factors GATA-4 and GATA-6 and a GATA family cofactor, FOG- 2, are expressed in human ovary and sex cord-derived ovarian tumors. J Clin Endocrinol Metab 85:3476–3483 [PubMed] [Google Scholar]
• Gillio-Meina C, Hui YY, LaVoie HA 2003 GATA-4 and GATA-6 transcription factors: expression, immunohistochemical localization, and possible function in the porcine ovary. Biol Reprod 68:412–422 [PubMed] [Google Scholar]
• McGee EA, Hsueh AJ 2000 Initial and cyclic recruitment of ovarian follicles. Endocr Rev 21:200–214 [PubMed] [Google Scholar]
• Vaskivuo TE, Aittomaki K, Anttonen M, Ruokonen A, Herva R, Osawa Y, Heikinheimo M, Huhtaniemi I, Tapanainen JS 2002 Effects of follicle-stimulating hormone (FSH) and human chorionic gonadotropin in individuals with an inactivating mutation of the FSH receptor. Fertil Steril 78:108–113 [PubMed] [Google Scholar]
• Balla A, Danilovich N, Yang Y, Sairam MR 2003 Dynamics of ovarian development in the FORKO immature mouse: structural and functional implications for ovarian reserve. Biol Reprod 69:1281–1293 [PubMed] [Google Scholar]
• Perlman S, Bouquin T, van den HB, Jensen TH, Schambye HT, Knudsen S, Okkels JS 2006 Transcriptome analysis of FSH and FSH variant stimulation in granulosa cells from IVM patients reveals novel regulated genes. Mol Hum Reprod 12:135–144 [PubMed] [Google Scholar]
• Brown CO, III, Chi X, Garcia-Gras E, Shirai M, Feng XH, Schwartz RJ 2004 The cardiac determination factor, Nkx2–5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer. J Biol Chem 279:10659–10669 [PubMed] [Google Scholar]
• Blokzijl A, ten Dijke P, Ibanez CF 2002 Physical and functional interaction between GATA-3 and Smad3 allows TGF-β regulation of GATA target genes. Curr Biol 12:35–45 [PubMed] [Google Scholar]
• Anttonen M, Parviainen H, Kyronlahti A, Bielinska M, Wilson DB, Ritvos O, Heikinheimo M 2006 GATA-4 is a granulosa cell factor employed in inhibin-α activation by the TGF-β pathway. J Mol Endocrinol 36:557–568 [PubMed] [Google Scholar]
• Silverman E, Eimerl S, Orly J 1999 CCAAT enhancer-binding protein β and GATA-4 binding regions within the promoter of the steroidogenic acute regulatory protein (StAR) gene are required for transcription in rat ovarian cells. J Biol Chem 274:17987–17996 [PubMed] [Google Scholar]
• Silverman E, Yivgi-Ohana N, Sher N, Bell M, Eimerl S, Orly J 2006 Transcriptional activation of the steroidogenic acute regulatory protein (StAR) gene: GATA-4 and CCAAT/enhancer-binding protein β confer synergistic responsiveness in hormone-treated rat granulosa and HEK293 cell models. Mol Cell Endocrinol 252:92–101 [PubMed] [Google Scholar]
• Hiroi H, Christenson LK, Chang L, Sammel MD, Berger SL, Strauss III JF 2004 Temporal and spatial changes in transcription factor binding and histone modifications at the steroidogenic acute regulatory protein (stAR) locus associated with stAR transcription. Mol Endocrinol 18:791–806 [PubMed] [Google Scholar]
• Cheng CK, Yeung CM, Chow BK, Leung PC 2002 Characterization of a new upstream GnRH receptor promoter in human ovarian granulosa-luteal cells. Mol Endocrinol 16:1552–1564 [PubMed] [Google Scholar]
• Cai Z, Kwintkiewicz J, Young ME, Stocco C 2007 Prostaglandin E2 increases cyp19 expression in rat granulosa cells: implication of GATA-4. Mol Cell Endocrinol 263:181–189 [PMC free article] [PubMed] [Google Scholar]
• Stocco C, Kwintkiewicz J, Cai Z 2007 Identification of regulatory elements in the Cyp19 proximal promoter in rat luteal cells. J Mol Endocrinol 39:211–221 [PubMed] [Google Scholar]
• Brown KA, Sayasith K, Bouchard N, Lussier JG, Sirois J 2007 Molecular cloning of equine 17β-hydroxysteroid dehydrogenase type 1 and its downregulation during follicular luteinization in vivo. J Mol Endocrinol 38:67–78 [PubMed] [Google Scholar]
• Sher N, Yivgi-Ohana N, Orly J 2007 Transcriptional regulation of the cholesterol side chain cleavage cytochrome P450 gene (CYP11A1) revisited: binding of GATA, cyclic adenosine 3′,5′-monophosphate response element-binding protein and activating protein (AP)-1 proteins to a distal novel cluster of cis-regulatory elements potentiates AP-2 and steroidogenic factor-1-dependent gene expression in the rodent placenta and ovary. Mol Endocrinol 21:948–962 [PubMed] [Google Scholar]
• Tremblay JJ, Robert NM, Viger RS 2001 Modulation of endogenous GATA-4 activity reveals its dual contribution to Müllerian inhibiting substance gene transcription in Sertoli cells. Mol Endocrinol 15:1636–1650 [PubMed] [Google Scholar]
• Watanabe K, Clarke TR, Lane AH, Wang X, Donahoe PK 2000 Endogenous expression of Mullerian inhibiting substance in early postnatal rat Sertoli cells requires multiple steroidogenic factor-1 and GATA-4-binding sites. Proc Natl Acad Sci USA 97:1624–1629 [PMC free article] [PubMed] [Google Scholar]
• Teixeira J, Maheswaran S, Donahoe PK 2001 Mullerian inhibiting substance: an instructive developmental hormone with diagnostic and possible therapeutic applications. Endocr Rev 22:657–674 [PubMed] [Google Scholar]
• Ng YK, George KM, Engel JD, Linzer DI 1994 GATA factor activity is required for the trophoblast-specific transcriptional regulation of the mouse placental lactogen I gene. Development 120:3257–3266 [PubMed] [Google Scholar]
• Liang R, Limesand SW, Anthony RV 1999 Structure and transcriptional regulation of the ovine placental lactogen gene. Eur J Biochem 265:883–895 [PubMed] [Google Scholar]
• Ma GT, Roth ME, Groskopf JC, Tsai FY, Orkin SH, Grosveld F, Engel JD, Linzer DI 1997 GATA-2 and GATA-3 regulate trophoblast-specific gene expression in vivo. Development 124:907–914 [PubMed] [Google Scholar]
• Jackson D, Volpert OV, Bouck N, Linzer DI 1994 Stimulation and inhibition of angiogenesis by placental proliferin and proliferin-related protein. Science 266:1581–1584 [PubMed] [Google Scholar]
• Shi D, Winston JH, Blackburn MR, Datta SK, Hanten G, Kellems RE 1997 Diverse genetic regulatory motifs required for murine adenosine deaminase gene expression in the placenta. J Biol Chem 272:2334–2341 [PubMed] [Google Scholar]
• Wang Z, Melmed S 1998 Functional map of a placenta-specific enhancer of the human leukemia inhibitory factor receptor gene. J Biol Chem 273:26069–26077 [PubMed] [Google Scholar]
• Cheng KW, Chow BK, Leung PC 2001 Functional mapping of a placenta-specific upstream promoter for human gonadotropin-releasing hormone receptor gene. Endocrinology 142:1506–1516 [PubMed] [Google Scholar]
• Piao YS, Peltoketo H, Vihko P, Vihko R 1997 The proximal promoter region of the gene encoding human 17β-hydroxysteroid dehydrogenase type 1 contains GATA, AP-2, and Sp1 response elements: analysis of promoter function in choriocarcinoma cells. Endocrinology 138:3417–3425 [PubMed] [Google Scholar]
• Peng L, Huang Y, Jin F, Jiang SW, Payne AH 2004 TEF-5 and a GATA-like protein determine placental-specific expression of the type I human 3β-hydroxysteroid dehydrogenase gene, HSD3B1. Mol Endocrinol 18:2049–2060 [PMC free article] [PubMed] [Google Scholar]
• Else T, Hammer GD 2005 Genetic analysis of adrenal absence: agenesis and aplasia. Trends Endocrinol Metab 16:458–468 [PubMed] [Google Scholar]
• Keegan CE, Hammer GD 2002 Recent insights into organogenesis of the adrenal cortex. Trends Endocrinol Metab 13:200–208 [PubMed] [Google Scholar]
• Kiiveri S, Liu J, Westerholm-Ormio M, Narita N, Wilson DB, Voutilainen R, Heikinheimo M 2002 Differential expression of GATA-4 and GATA-6 in fetal and adult mouse and human adrenal tissue. Endocrinology 143:3136–3143 [PubMed] [Google Scholar]
• Nemer G, Nemer M 2003 Transcriptional activation of BMP-4 and regulation of mammalian organogenesis by GATA-4 and -6. Dev Biol 254:131–148 [PubMed] [Google Scholar]
• Jimenez P, Saner K, Mayhew B, Rainey WE 2003 GATA-6 is expressed in the human adrenal and regulates transcription of genes required for adrenal androgen biosynthesis. Endocrinology 144:4285–4288 [PubMed] [Google Scholar]
• Kiiveri S, Siltanen S, Rahman N, Bielinska M, Lehto VP, Huhtaniemi IT, Muglia LJ, Wilson DB, Heikinheimo M 1999 Reciprocal changes in the expression of transcription factors GATA-4 and GATA-6 accompany adrenocortical tumorigenesis in mice and humans. Mol Med 5:490–501 [PMC free article] [PubMed] [Google Scholar]
• Keeney DS, Jenkins CM, Waterman MR 1995 Developmentally regulated expression of adrenal 17α-hydroxylase cytochrome P450 in the mouse embryo. Endocrinology 136:4872–4879 [PubMed] [Google Scholar]
• Huang N, Dardis A, Miller WL 2005 Regulation of cytochrome b5 gene transcription by Sp3, GATA-6, and steroidogenic factor 1 in human adrenal NCI-H295A cells. Mol Endocrinol 19:2020–2034 [PubMed] [Google Scholar]
• Saner KJ, Suzuki T, Sasano H, Pizzey J, Ho C, Strauss III JF, Carr BR, Rainey WE 2005 Steroid sulfotransferase 2A1 gene transcription is regulated by steroidogenic factor 1 and GATA-6 in the human adrenal. Mol Endocrinol 19:184–197 [PubMed] [Google Scholar]
• Huang YH, Lee CY, Tai PJ, Yen CC, Liao CY, Chen WJ, Liao CJ, Cheng WL, Chen RN, Wu SM, Wang CS, Lin KH 2006 Indirect regulation of human dehydroepiandrosterone sulfotransferase family 1A member 2 by thyroid hormones. Endocrinology 147:2481–2489 [PubMed] [Google Scholar]
• Suzuki E, Evans T, Lowry J, Truong L, Bell DW, Testa JR, Walsh K 1996 The human GATA-6 gene: structure, chromosomal location, and regulation of expression by tissue-specific and mitogen-responsive signals. Genomics 38:283–290 [PubMed] [Google Scholar]
• Nagata D, Suzuki E, Nishimatsu H, Yoshizumi M, Mano T, Walsh K, Sata M, Kakoki M, Goto A, Omata M, Hirata Y 2000 Cyclin A downregulation and p21(cip1) upregulation correlate with GATA-6-induced growth arrest in glomerular mesangial cells. Circ Res 87:699–704 [PubMed] [Google Scholar]
• Bielinska M, Parviainen H, Porter-Tinge SB, Kiiveri S, Genova E, Rahman N, Huhtaniemi IT, Muglia LJ, Heikinheimo M, Wilson DB 2003 Mouse strain susceptibility to gonadectomy-induced adrenocortical tumor formation correlates with the expression of GATA-4 and luteinizing hormone receptor. Endocrinology 144:4123–4133 [PubMed] [Google Scholar]
• Achermann JC, Ito M, Hindmarsh PC, Jameson JL 1999 A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22:125–126 [PubMed] [Google Scholar]
• Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, Jameson JL 2002 Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab 87:1829–1833 [PubMed] [Google Scholar]
• Correa RV, Domenice S, Bingham NC, Billerbeck AE, Rainey WE, Parker KL, Mendonca BB 2004 A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency. J Clin Endocrinol Metab 84:1767–1772 [PubMed] [Google Scholar]
• Tremblay JJ, Viger RS 2003 A mutated form of steroidogenic factor 1 (SF-1 G35E) that causes sex reversal in humans fails to synergize with transcription factor GATA-4. J Biol Chem 278:42637–42642 [PubMed] [Google Scholar]
• Finelli P, Pincelli AI, Russo S, Bonati MT, Recalcati MP, Masciadri M, Giardino D, Cavagnini F, Larizza L 2007 Disruption of friend of GATA 2 gene (FOG-2) by a de novo t(8;10) chromosomal translocation is associated with heart defects and gonadal dysgenesis. Clin Genet 71:195–204 [PubMed] [Google Scholar]
• Wood JR, Nelson VL, Ho C, Jansen E, Wang CY, Urbanek M, McAllister JM, Mosselman S, Strauss III JF 2003 The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem 278:26380–26390 [PubMed] [Google Scholar]
• Wood JR, Ho CK, Nelson-Degrave VL, McAllister JM, Strauss III JF 2004 The molecular signature of polycystic ovary syndrome (PCOS) theca cells defined by gene expression profiling. J Reprod Immunol 63:51–60 [PubMed] [Google Scholar]
• Ho CK, Wood JR, Stewart DR, Ewens K, Ankener W, Wickenheisser J, Nelson-Degrave V, Zhang Z, Legro RS, Dunaif A, McAllister JM, Spielman R, Strauss III JF 2005 Increased transcription and increased messenger ribonucleic acid (mRNA) stability contribute to increased GATA6 mRNA abundance in polycystic ovary syndrome theca cells. J Clin Endocrinol Metab 90:6596–6602 [PubMed] [Google Scholar]
• Lassus H, Laitinen MP, Anttonen M, Heikinheimo M, Aaltonen LA, Ritvos O, Butzow R 2001 Comparison of serous and mucinous ovarian carcinomas: distinct pattern of allelic loss at distal 8p and expression of transcription factor GATA-4. Lab Invest 81:517–526 [PubMed] [Google Scholar]
• Caslini C, Capo-chichi CD, Roland IH, Nicolas E, Yeung AT, Xu XX 2006 Histone modifications silence the GATA transcription factor genes in ovarian cancer. Oncogene 25:5446–5461 [PMC free article] [PubMed] [Google Scholar]
• Wakana K, Akiyama Y, Aso T, Yuasa Y 2006 Involvement of GATA-4/-5 transcription factors in ovarian carcinogenesis. Cancer Lett 241:281–288 [PubMed] [Google Scholar]
• Capo-chichi CD, Roland IH, Vanderveer L, Bao R, Yamagata T, Hirai H, Cohen C, Hamilton TC, Godwin AK, Xu XX 2003 Anomalous expression of epithelial differentiation-determining GATA factors in ovarian tumorigenesis. Cancer Res 63:4967–4977 [PubMed] [Google Scholar]
• Schumer ST, Cannistra SA 2003 Granulosa cell tumor of the ovary. J Clin Oncol 21:1180–1189 [PubMed] [Google Scholar]
• Fuller PJ, Chu S 2004 Signalling pathways in the molecular pathogenesis of ovarian granulosa cell tumours. Trends Endocrinol Metab 15:122–128 [PubMed] [Google Scholar]
• Perlman H, Suzuki E, Simonson M, Smith RC, Walsh K 1998 GATA-6 induces p21(Cip1) expression and G1 cell cycle arrest. J Biol Chem 273:13713–13718 [PubMed] [Google Scholar]
• Kobayashi S, Lackey T, Huang Y, Bisping E, Pu WT, Boxer LM, Liang Q 2006 Transcription factor gata4 regulates cardiac BCL2 gene expression in vitro and in vivo. FASEB J 20:800–802 [PubMed] [Google Scholar]
• Suzuki YJ, Day RM, Tan CC, Sandven TH, Liang Q, Molkentin JD, Fanburg BL 2003 Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells. J Biol Chem 278:17525–17531 [PubMed] [Google Scholar]
• Aries A, Paradis P, Lefebvre C, Schwartz RJ, Nemer M 2004 Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity. Proc Natl Acad Sci USA 101:6975–6980 [PMC free article] [PubMed] [Google Scholar]
• Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA 1996 Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384:470–474 [PubMed] [Google Scholar]
• Burns KH, Agno JE, Sicinski P, Matzuk MM 2003 Cyclin D2 and p27 are tissue-specific regulators of tumorigenesis in inhibin α knockout mice. Mol Endocrinol 17:2053–2069 [PubMed] [Google Scholar]
• Ito M, Achermann JC, Jameson JL 2000 A naturally occurring steroidogenic factor-1 mutation exhibits differential binding and activation of target genes. J Biol Chem 275:31708–31714 [PubMed] [Google Scholar]
• Kiiveri S, Liu J, Heikkila P, Arola J, Lehtonen E, Voutilainen R, Heikinheimo M 2004 Transcription factors GATA-4 and GATA-6 in human adrenocortical tumors. Endocr Res 30:919–923 [PubMed] [Google Scholar]
• Kiiveri S, Liu J, Arola J, Heikkila P, Kuulasmaa T, Lehtonen E, Voutilainen R, Heikinheimo M 2005 Transcription factors GATA-6, SF-1, and cell proliferation in human adrenocortical tumors. Mol Cell Endocrinol 233:47–56 [PubMed] [Google Scholar]
• Bassett MH, Mayhew B, Rehman K, White PC, Mantero F, Arnaldi G, Stewart PM, Bujalska I, Rainey WE 2005 Expression profiles for steroidogenic enzymes in adrenocortical disease. J Clin Endocrinol Metab 90:5446–5455 [PubMed] [Google Scholar]
• Barbosa AS, Giacaglia LR, Martin RM, Mendonca BB, Lin CJ 2004 Assessment of the role of transcript for GATA-4 as a marker of unfavorable outcome in human adrenocortical neoplasms. BMC Endocr Disord 4:3 [PMC free article] [PubMed] [Google Scholar]
• Bielinska M, Kiiveri S, Parviainen H, Mannisto S, Heikinheimo M, Wilson DB 2006 Gonadectomy-induced adrenocortical neoplasia in the domestic ferret (Mustela putorius furo) and laboratory mouse. Vet Pathol 43:97–117 [PubMed] [Google Scholar]
• Murthy AS, Russfield AB 1970 Endocrine changes in two strains of mice exposed to constant illumination. Endocrinology 86:914–917 [PubMed] [Google Scholar]
• Bielinska M, Genova E, Boime I, Parviainen H, Kiiveri S, Rahman N, Leppaluoto J, Heikinheimo M, Wilson DB 2004 Nude mice as a model for gonadotropin-induced adrenocortical neoplasia. Endocr Res 30:913–917 [PubMed] [Google Scholar]
• Jabara S, Christenson LK, Wang CY, McAllister JM, Javitt NB, Dunaif A, Strauss III JF 2003 Stromal cells of the human postmenopausal ovary display a distinctive biochemical and molecular phenotype. J Clin Endocrinol Metab 88:484–492 [PubMed] [Google Scholar]
• Rosner JM, Charreau E, Houssay AB, Epper C 1966 Biosynthesis of sexual steroids by hyperplastic adrenal glands of castrated female C3H/Ep mice. Endocrinology 79:681–686 [PubMed] [Google Scholar]
• Kaaijk EM, Sasano H, Suzuki T, Beek JF, van der Veen F 2000 Distribution of steroidogenic enzymes involved in androgen synthesis in polycystic ovaries: an immunohistochemical study. Mol Hum Reprod 6:443–447 [PubMed] [Google Scholar]
• Rahman NA, Kiiveri S, Rivero-Muller A, Levallet J, Vierre S, Kero J, Wilson DB, Heikinheimo M, Huhtaniemi I 2004 Adrenocortical tumorigenesis in transgenic mice expressing the inhibin α-subunit promoter/simian virus 40 T-antigen transgene: relationship between ectopic expression of luteinizing hormone receptor and transcription factor GATA-4. Mol Endocrinol 18:2553–2569 [PubMed] [Google Scholar]
• Kananen K, Markkula M, Mikola M, Rainio EM, McNeilly A, Huhtaniemi I 1996 Gonadectomy permits adrenocortical tumorigenesis in mice transgenic for the mouse inhibin α-subunit promoter/simian virus 40 T-antigen fusion gene: evidence for negative autoregulation of the inhibin α-subunit gene. Mol Endocrinol 10:1667–1677 [PubMed] [Google Scholar]
• Russfield AB 1975 Experimental endocrinopathies. Methods Achiev Exp Pathol 7:132–148 [PubMed] [Google Scholar]
• Peterson RA, Kiupel M, Bielinska M, Kiiveri S, Heikinheimo M, Capen CC, Wilson DB 2004 Transcription factor GATA-4 is a marker of anaplasia in adrenocortical neoplasms of the domestic ferret (Mustela putorius furo). Vet Pathol 41:446–449 [PubMed] [Google Scholar]
• Hietakangas V, Anckar J, Blomster HA, Fujimoto M, Palvimo JJ, Nakai A, Sistonen L 2006 PDSM, a motif for phosphorylation-dependent SUMO modification. Proc Natl Acad Sci USA 103:45–50 [PMC free article] [PubMed] [Google Scholar]
• Collavin L, Gostissa M, Avolio F, Secco P, Ronchi A, Santoro C, Del Sal G 2004 Modification of the erythroid transcription factor GATA-1 by SUMO-1. Proc Natl Acad Sci USA 101:8870–8875 [PMC free article] [PubMed] [Google Scholar]
• Chun TH, Itoh H, Subramanian L, Iniguez-Lluhi JA, Nakao K 2003 Modification of GATA-2 transcriptional activity in endothelial cells by the SUMO E3 ligase PIASy. Circ Res 92:1201–1208 [PubMed] [Google Scholar]
• Wang J, Feng XH, Schwartz RJ 2004 SUMO-1 modification activated GATA4-dependent cardiogenic gene activity. J Biol Chem 279:49091–49098 [PubMed] [Google Scholar]
• Komatsu T, Mizusaki H, Mukai T, Ogawa H, Baba D, Shirakawa M, Hatakeyama S, Nakayama KI, Yamamoto H, Kikuchi A, Morohashi K 2004 Small ubiquitin-like modifier 1 (SUMO-1) modification of the synergy control motif of Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) regulates synergistic transcription between Ad4BP/SF-1 and Sox9. Mol Endocrinol 18:2451–2462 [PubMed] [Google Scholar]
• Boyes J, Byfield P, Nakatani Y, Ogryzko V 1998 Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 396:594–598 [PubMed] [Google Scholar]
• Hung HL, Lau J, Kim AY, Weiss MJ, Blobel GA 1999 CREB-binding protein acetylates hematopoietic transcription factor GATA-1 at functionally important sites. Mol Cell Biol 19:3496–3505 [PMC free article] [PubMed] [Google Scholar]
• Hayakawa F, Towatari M, Ozawa Y, Tomita A, Privalsky ML, Saito H 2004 Functional regulation of GATA-2 by acetylation. J Leukoc Biol 75:529–540 [PubMed] [Google Scholar]
• Yamagata T, Mitani K, Oda H, Suzuki T, Honda H, Asai T, Maki K, Nakamoto T, Hirai H 2000 Acetylation of GATA-3 affects T-cell survival and homing to secondary lymphoid organs. EMBO J 19:4676–4687 [PMC free article] [PubMed] [Google Scholar]
• Crossley M, Orkin SH 1994 Phosphorylation of the erythroid transcription factor GATA-1. J Biol Chem 269:16589–16596 [PubMed] [Google Scholar]
• Hernandez-Hernandez A, Ray P, Litos G, Ciro M, Ottolenghi S, Beug H, Boyes J 2006 Acetylation and MAPK phosphorylation cooperate to regulate the degradation of active GATA-1. EMBO J 25:3264–3274 [PMC free article] [PubMed] [Google Scholar]
• Towatari M, May GE, Marais R, Perkins GR, Marshall CJ, Cowley S, Enver T 1995 Regulation of GATA-2 phosphorylation by mitogen-activated protein kinase and interleukin-3. J Biol Chem 270:4101–4107 [PubMed] [Google Scholar]
• Menghini R, Marchetti V, Cardellini M, Hribal ML, Mauriello A, Lauro D, Sbraccia P, Lauro R, Federici M 2005 Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis. Circulation 111:1946–1953 [PubMed] [Google Scholar]
• Koga S, Yamaguchi N, Abe T, Minegishi M, Tsuchiya S, Yamamoto M, Minegishi N 2007 Cell-cycle-dependent oscillation of GATA2 expression in hematopoietic cells. Blood 109:4200–4208 [PubMed] [Google Scholar]
• Bouchard MF, Taniguchi H, Viger RS 2005 Protein kinase A-dependent synergism between GATA factors and the nuclear receptor, liver receptor homolog-1, regulates human aromatase (CYP19) PII promoter activity in breast cancer cells. Endocrinology 146:4905–4916 [PubMed] [Google Scholar]
• Chen CH, Zhang DH, LaPorte JM, Ray A 2000 Cyclic AMP activates p38 mitogen-activated protein kinase in Th2 cells: phosphorylation of GATA-3 and stimulation of Th2 cytokine gene expression. J Immunol 165:5597–5605 [PubMed] [Google Scholar]
• Maneechotesuwan K, Xin Y, Ito K, Jazrawi E, Lee KY, Usmani OS, Barnes PJ, Adcock IM 2007 Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J Immunol 178:2491–2498 [PubMed] [Google Scholar]
• Gordon DF, Tucker EA, Tundwal K, Hall H, Wood WM, Ridgway EC 2006 MED220/thyroid receptor-associated protein 220 functions as a transcriptional coactivator with Pit-1 and GATA-2 on the thyrotropin-β promoter in thyrotropes. Mol Endocrinol 20:1073–1089 [PubMed] [Google Scholar]
• Feng ZM, Wu AZ, Zhang Z, Chen CL 2000 GATA-1 and GATA-4 transactivate inhibin/activin β-B-subunit gene transcription in testicular cells. Mol Endocrinol 14:1820–1835 [PubMed] [Google Scholar]
• Lei N, Heckert LL 2004 Gata4 regulates testis expression of Dmrt1. Mol Cell Biol 24:377–388 [PMC free article] [PubMed] [Google Scholar]
• Hermann BP, Heckert LL 2005 Silencing of Fshr occurs through a conserved, hypersensitive site in the first intron. Mol Endocrinol 19:2112–2131 [PMC free article] [PubMed] [Google Scholar]
• Kim JS, Griswold MD 2001 E2F and GATA-1 are required for the Sertoli cell-specific promoter activity of the follicle-stimulating hormone receptor gene. J Androl 22:629–639 [PubMed] [Google Scholar]
• Cheng CK, Cheung CH, Lee WM 2003 Mouse testin: complementary DNA cloning, genomic organization, and characterization of its proximal promoter region. Biol Reprod 68:1376–1386 [PubMed] [Google Scholar]
• Feng ZM, Wu AZ, Chen CL 1998 Testicular GATA-1 factor up-regulates the promoter activity of rat inhibin α-subunit gene in MA-10 Leydig tumor cells. Mol Endocrinol 12:378–390 [PubMed] [Google Scholar]
• Wooton-Kee CR, Clark BJ 2000 Steroidogenic factor-1 influences protein-deoxyribonucleic acid interactions within the cyclic adenosine 3,5-monophosphate-responsive regions of the murine steroidogenic acute regulatory protein gene. Endocrinology 141:1345–1355 [PubMed] [Google Scholar]
• Xu W, Murphy LJ 2000 Cloning of the mouse Pax4 gene promoter and identification of a pancreatic β-cell specific enhancer. Mol Cell Endocrinol 170:79–893 [PubMed] [Google Scholar]