Dax-1 as One of the Target Genes of Ad4BP/SF-1

Kawabe, Ken; Shikayama, Tatsuji; Tsuboi, Hisae; Oka, Sanae; Oba, Koichi; Yanase, Toshihiko; Nawata, Hajime; Morohashi, Ken-ichirou

doi:10.1210/mend.13.8.0325

Cited by 98 publications

(12 citation statements)

References 71 publications

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“…Consequently, decreased corticosterone output by SF-1 ϩ͞Ϫ adrenals might result not only from reduced adrenal size, but also from decreased expression of SF-1 target genes, such as the steroidogenic acute regulatory protein (StAR), the steroid hydroxylases (including P450scc) (7), the ACTH receptor (MC2-R) (20), and Dax1 (21). As expected, SF-1 mRNA and protein levels were reduced in SF-1 ϩ͞Ϫ adrenals.…”

Section: Loss Of One Sf-1 Allele Results In Adrenal Hypoplasia and Almentioning

confidence: 69%

Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response

Bland

Jamieson

Akana

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

167

118

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Adrenal steroids are essential for homeostasis and survival during severe physiological stress. Analysis of a patient heterozygous for the steroidogenic factor-1 (SF-1) gene suggested that reduced expression of this nuclear receptor leads to adrenal failure. We therefore examined SF-1 heterozygous (؉͞؊) mice as a potential model for delineating mechanisms underlying this disease. Here we show that SF-1 ؉͞؊ mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting steroidogenic protein StAR, help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF-1 heterozygotes are revealed under stressful conditions, demonstrating that normal gene dosage of SF-1 is required for mounting an adequate stress response. Our findings predict that natural variations leading to reduced SF-1 function may underlie some forms of subclinical adrenal insufficiency, which become life threatening during traumatic stress. P hysiological adaptation to infection, injury, and starvation requires an endocrine stress response that is mediated by the hypothalamic-pituitary-adrenal (HPA) axis. In instances of adrenal crisis or adrenal insufficiency, the inability to mount an adequate response to acute physiological stress can lead to morbidity (1). In response to stress, adrenal secretion of glucocorticoids is initiated by the hypothalamic neuropeptide corticotropin releasing hormone (CRH), which stimulates pituitary release of adrenocorticotropic hormone (ACTH). Activation of ACTH receptors in the adrenal cortex promotes glucocorticoid synthesis and secretion; glucocorticoids then act on a wide range of target tissues (2). Human diseases associated with an impaired stress response arise from either primary defects in the adrenal or secondary defects at the level of the hypothalamus or pituitary. Primary adrenal insufficiency is most commonly due to bilateral adrenal gland destruction resulting from autoimmune and infectious diseases, such as AIDS and tuberculosis (1). Other forms of primary adrenal insufficiency result from inherited defects in cortisol biosynthesis and manifest as adrenal hyperplasia because of lack of adrenal feedback in the HPA axis (1). Finally, rarer forms of familial adrenal insufficiency are associated with mutations in members of the nuclear receptor superfamily. For example, mutations in the X-linked gene Dax1 lead to abnormal adrenal development resulting in adrenal hypoplasia, as well as hypogonadotropic hypogonadism (3-5).A similar, but less well-characterized form of adrenal insufficiency was revealed by the analysis of a single patient with a heterozygous mutation in the orphan nuclear receptor steroidogenic factor-1 (SF-1). This individual was diagnosed with primary adrenal insufficiency as well as XY sex reversal, suggesting that SF-1 functions in a dose-dependent manner in humans (6). A large number...

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Section: Loss Of One Sf-1 Allele Results In Adrenal Hypoplasia and Almentioning

confidence: 69%

Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response

Bland

Jamieson

Akana

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

167

118

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“…Multiple evidence suggests key roles for DAX-1 in mammalian sex development, reproduction, and steroidogenesis (28 -33). DAX-1 is predominantly expressed in adrenal, ovary, testes, hypothalamus, and pituitary and functionally antagonizes SF-1, an essential orphan receptor for the development of the hypothalamic-pituitary-gonadal axis and regulator of male-specific gene expression (27,28,30,(32)(33)(34)(35). Together with demonstration of direct interaction, these findings suggest DAX-1 specifically acts as a cofactor for 32).…”

mentioning

confidence: 79%

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

Zhang¹,

Thomsen

Johansson

et al. 2000

Journal of Biological Chemistry

154

127

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We have discovered that the orphan receptor DAX-1 (NROB1) interacts with the estrogen receptors ER␣ and ER␤. Interaction occurs with ligand-activated ERs in solution and on DNA and is mediated by the unique DAX-1 N-terminal repeat domain. Each of the three repeats contains a leucine-rich receptor-binding motif, known as the LXXLL motif, which is usually found in nuclear receptor coactivators. We have demonstrated that DAX-1 functions as an inhibitor of ER activation in mammalian cells and suggest a mechanism involving two sequential events, occupation of the ligand-induced coactivator-binding surface and subsequent recruitment of corepressors. Accordingly, we propose that DAX-1 itself acts as a corepressor for ERs. Because DAX-1 is coexpressed with ERs in reproductive tissues, these interactions could play significant roles by influencing estrogen signaling pathways. Our results point at functional similarities between DAX-1 and the orphan receptor SHP (NROB2) in that they have acquired features of transcriptional coregulators that are unique for members of the nuclear receptor family.To transduce hormone and metabolic signaling to target genes, nuclear receptors require transcriptional cofactors that are collectively referred to as coregulators (1). These proteins exist in multiple complexes, possess multiple enzymatic activities, and bridge receptors to chromatin components or to the basal transcription machinery or to both. Multiple candidate proteins exist that are believed to be critical for the proper function of nuclear receptor signaling (1-3). The majority of coregulators bind to the receptor ligand-binding domain (LBD), 1 which is able to adopt different conformations depending on the ligand status and thereby discriminate between coactivators and corepressors. Functional and structural studies in particular elucidated the precise mechanisms of coactivator interaction with the ligand-inducible activation domain (AF-2) via short leucine motifs known as LXXLL or NR-Box (4 -8).We became interested in coregulators in particular that influence the transcriptional activity of estrogen receptors (ER). Two related subtypes, ER␣ and ER␤, play crucial roles in sex development and reproduction in multiple physiological processes as well as in cancer (9 -11). Previous research has provided detailed insights into structural and functional aspects of their interplay with coregulators (8,(12)(13)(14). Although agonist binding usually is associated with ER activation caused by coactivator recruitment, regulatory mechanisms have been proposed that could play a role in modulation and feedback control of estrogen signaling (15, 16). Recent work has revealed an unexpected role of the orphan receptor SHP (NROB2) in inhibiting transactivation of ERs (17, 18). Particularly, we have provided evidence that SHP, which consists only of an LBD and thus cannot bind target genes directly, has instead acquired a novel coregulator function by antagonizing the interactions of ERs with associated coactivators (18,19).The closest relati...

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“…Up-regulation of the SF-1 target gene Dax-1 in cells from this patient suggests an interaction between SF-1 and Wnt signaling on the Dax-1 promoter (41), as recently confirmed by the demonstration of synergy between SF-1 and ␤-catenin on activation of Dax-1 transcription in the developing female gonad (42). Because knockout of the SF-1 target gene, ␣-inhibin results in a syndrome of gonadal and adrenal sex steroid excess similar to the Wnt-4-null mice, and transcription of ␣-inhibin, like Dax-1 (43), is absolutely dependent upon SF-1, we hypothesized that components of the Wnt signaling cascade directly interact with SF-1 to regulate the ␣-inhibin promoter in the adrenal cortex (44 -46). In this article we have specifically explored the activation of SF-1-dependent transcription of the ␣-inhibin gene by ␤-catenin in the adrenal cortex.…”

mentioning

confidence: 79%

Convergence of Wnt Signaling and Steroidogenic Factor-1 (SF-1) on Transcription of the Rat Inhibin α Gene

Gummow

Winnay

Hammer

2003

Journal of Biological Chemistry

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The action of a variety of peptide hormones is critical for proper growth and differentiation of the urogenital ridge, which ultimately gives rise to the kidney, adrenal cortex, and gonad. One such class of peptides is the Wnt family of secreted glycoproteins that is classically involved in development of cell polarity and cell fate determination. Notably, alterations in Wnt-4 expression in mice and humans result in profound defects in urogenital ridge development, including dysregulation of kidney, gonadal, and adrenal growth. The nuclear receptor steroidogenic factor-1 (SF-1) has been implicated as a downstream effector of peptide hormone signaling during urogenital ridge development as evidenced by both the activation of SF-1-dependent transcription in the adrenal cortex by signaling molecules such as protein kinase A and by the adrenal and gonadal agenesis in mice with null mutations in SF-1. We hypothesized that Wnt-dependent signaling cascades regulate SF-1-dependent transcription of genes required for adrenogonadal development. Specifically, the data demonstrate that ␤-catenin synergizes with SF-1 to activate the ␣-inhibin promoter through formation of a transcriptional complex. The activation requires an intact SF-1 RE and is independent of TCF/Lef. These data support the recent observation that ␤-catenin can participate in nuclear receptor-mediated transcriptional activation and extend the findings to the monomer binding class of orphan nuclear receptors.

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Dax-1 as One of the Target Genes of Ad4BP/SF-1

Cited by 98 publications

References 71 publications

Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response

Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

Convergence of Wnt Signaling and Steroidogenic Factor-1 (SF-1) on Transcription of the Rat Inhibin α Gene

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