Generation of Two Distinct Functional Isoforms of Dosage-Sensitive Sex Reversal-Adrenal Hypoplasia Congenita-Critical Region on the X Chromosome Gene 1 (DAX-1) by Alternative Splicing

Hossain, Anwar; Chun, Li; Saunders, Grady F.

doi:10.1210/me.2003-0176

Cited by 38 publications

(41 citation statements)

References 28 publications

(40 reference statements)

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“…Dax-1A, or Dax-1␣, is a human Dax-1 splice variant in which the C-terminal 81 amino acids are replaced by a unique 12-amino-acid sequence (19,21). Dax-1␣ is unable to repress the SF-1-mediated induction of a reporter gene but instead can increase StAR promoter-luciferase gene expression when SF-1 is present in limiting amounts.…”

Section: Discussionmentioning

confidence: 99%

Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis

Yang

Gerin

et al. 2009

Molecular and Cellular Biology

104

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Nuclear hormone receptors (NRs) mediate the transcriptional responses to a wide variety of physiological stimuli and thus function as important regulators of development, metabolism, and reproduction. By binding to specific DNA sequences, NRs serve as platforms for the recruitment of various coregulatory factors that effect gene regulation. Transcriptional coactivators often function either through their enzymatic activities (as in the examples of acetyl and methyl transferases) or through the formation of productive complexes with the basal transcription machinery. In contrast, corepressors often have enzymatic activities opposite those of coactivators, such as those of deactylases and demethylases. Thus, coregulators, by functioning as coactivators or corepressors of NR activity, play pivotal roles in mediating hormone action (reviewed in references 13 and 42).The best-characterized coactivators are the p160 family proteins SRC-1 (NCoA1), TIF2 (GRIP1/NCoA2/SRC-2), and AIB1 (pCIP/ACTR/NCoA3/SRC-3) (3, 51, 62, 66). These coactivators harbor autonomous activation domains and NR interaction domains (28,65). Recently, the steroid receptor RNA activator (SRA) has been characterized as the only known coregulator that can function as an RNA (36). SRA was shown to coactivate glucocorticoid receptors without direct physical interaction, as part of a ribonucleoprotein complex with p160 coactivators. In addition, SRA coactivates retinoic acid receptors, and this function is dependent upon SRA pseudouridinylation (78). SRA also functions as a thyroid hormone receptor (TR) coactivator by direct physical interaction (72). The TR SRA binding domain is a 41-amino-acid region located between the second zinc finger and the ligand binding domain. Although SRA-protein interactions play important roles in NR activity, the molecular mechanisms and biological functions of these interactions remain largely unknown.Steroidogenic factor 1 (SF-1/NR5A1/Ad4BP) belongs to the NR5A subfamily of orphan NRs that bind DNA with high affinity as monomers. SF-1 plays critical roles in the regulation of sex determination, adrenal and gonadal development, reproductive function, and steroidogenesis (16,40,41,52,63). SF-1 interacts with several transcriptional coactivators, such as SRC-1 (11, 25), TIF2 (17), and p300 (9), resulting in the induction of a large number of genes including those for the adrenocorticotropin hormone (ACTH) receptor/melanocortin 2 receptor (Mc2R) and steroidogenic acute regulatory protein (StAR) (58, 70). We and others have shown that sumoylation inhibits and phosphorylation activates SF-1 (73), while recent structural analyses have revealed that phospholipids can serve as activating SF-1 ligands (33, 37).Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on X chromosome gene 1; NR0B1) is an unusual member of the nuclear receptor superfamily. Although the carboxyl-terminal region of Dax-1 is homologous to

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Section: Discussionmentioning

confidence: 99%

Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis

Yang

Gerin

et al. 2009

Molecular and Cellular Biology

104

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“…An alternatively spliced form of DAX1, called DAX1A, has recently been discovered (Ho et al, 2004;Hossain et al, 2004). Quantitative RT-PCR showed more DAX1A than DAX1 in all tissues in which it is expressed except testis where they are nearly equal.…”

Section: Alternatively Spliced Dax1amentioning

confidence: 99%

DAX1: Increasing complexity in the roles of this novel nuclear receptor

McCabe

2007

Molecular and Cellular Endocrinology

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SummaryDAX1 (NR0B1) is a nuclear receptor with a characteristic C-terminal ligand binding domain, but an atypical DNA binding domain. Mutations in the DAX1 gene cause adrenal hypoplasia congenita (AHC) establishing its biological importance. Recent studies highlight the complexities of DAX1 regulation and function. There is considerable phenotypic variability in AHC suggesting the existence of DAX1 modifier genes and environmental influences on DAX1 function. The findings of an alternatively spliced DAX1A, more common than DAX1 in all tissues except testis, of DAX1 homodimers, and of DAX1 heterodimers with a number of transcription factor partners including DAX1A and SHP point to an expanded transcription regulatory network under DAX1 control. Model organisms (mice and zebrafish) are being used to identify other DAX1 functions and modifier genes to understand the pathogenesis of AHC and the lack of genotype-phenotype correlation. KeywordsDAX1; NR0B1; Adrenal hypoplasia congenital; DAX1A; DAX1 homodimerization; DAX1 modifier genes DAX1 and Adrenal Hypoplasia Congenita (AHC)Mutations in DAX1 (NR0B1), which is encoded in the Xp21 chromosomal region a, can lead to adrenal insufficiency with glucocorticoid and mineralocorticoid deficiency (McCabe, 2001). These mutations are responsible for many, but not all, patients with the cytomegalic form of adrenal hypoplasia congenita (AHC). These mutations also cause hypogonadotropic hypogonadism (HH) which is consistent with the expression of DAX1 in the hypothalamus and pituitary.Duplications of the region of the X chromosome containing DAX1 cause dosage sensitive sex reversal (Bardoni et al., 1994;McCabe, 2001). Transgenic XY mice with additional copies of the mouse DAX1 ortholog expressed at high levels do not have male to female sex reversal, but do show delayed testicular development (Swain et al., 1998). When these investigators crossed the transgenic female mice with poschiavinus males who have a weaker male sex determining Sry allele, they did observe complete sex reversal.

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“…SHP has a short NTD with one 70 residue repeat, and DAX1 has a longer NTD containing 3.5 repeats [1,4]. An alternatively spliced isoform of DAX1, DAX1A, has been identified and contains an NTD similar to DAX1, but the CTD of DAX1A lacks the last 80 amino acids of the DAX1 CTD including theAF-2 domain, that is replaced by a novel 10-amino acid motif [5,6]. No alternatively spliced isoforms have been identified for SHP.…”

Section: Introductionmentioning

confidence: 99%

“…DAX1 may also have a role in bone cell development as well as early embryonic development [22][23][24]. DAX1A has a wider tissue expression profile than DAX1, as it is expressed in the adrenal gland, brain, ovary, pancreas, and testis, but the function of DAX1A in these tissues is unclear [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Hossain et al [6] showed that DAX1A interacts with SF1, and therefore suggest that DAX1A antagonizes DAX1 repression by competing with DAX1 for binding to SF1. We demonstrated the existence of DAX1-DAX1A heterodimers [26] and proposed an alternative mechanism whereby DAX1A interacts with DAX1 and prevents DAX1 from interacting with and/or repressing SF1.…”

Section: Introductionmentioning

confidence: 99%

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LXXLL motifs and AF-2 domain mediate SHP (NR0B2) homodimerization and DAX1 (NR0B1)–DAX1A heterodimerization

Iyer

Zhang²,

McCabe

2007

Molecular Genetics and Metabolism

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Small heterodimer partner (SHP; NR0B2) is an unusual orphan member of the nuclear receptor superfamily that functions as a corepressor of other nuclear receptors through heterodimeric interactions. Mutations in SHP are associated with mild obesity and insulin resistance. The protein domain structure of SHP is similar to Dosage-sensitive sex reversal adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1 (DAX1; NR0B1). Mutations in DAX1 cause AHC with associated hypogonadotropic hypogonadism. DAX1A is an alternatively spliced isoform of DAX1 that lacks the last 80 amino acids of the DAX1 C-terminal repressor domain and is replaced by a novel 10-amino acid motif. We have previously shown homodimerization of SHP and DAX1 individually, heterodimerization of DAX1 with SHP, and heterodimerization of DAX1 with DAX1A. In these studies, we investigated the domains and residues of SHP involved in SHP homodimerization and DAX1-SHP heterodimerization and also further characterized DAX1-DAX1 homodimerization and DAX1-DAX1A heterodimerization. We showed involvement of the SHP LXXLL motifs and AF-2 domain in SHP homodimerization and DAX1-SHP heterodimerization. We demonstrated redundancy of the LXXLL motifs in DAX1 homodimerization. While DAX1A subcellular localization is mostly cytoplasmic, DAX1-DAX1A heterodimers existed in the nucleus, suggesting differential functions for DAX1A in each compartment. We showed that the AF-2 domain of DAX1 is involved in DAX1-DAX1A heterodimerization. These results indicate that NR0B family members use similar mechanisms for homodimerization as well as heterodimerization. These resemble coactivator-receptor interactions that may have potential functional consequences for molecular mechanisms of the NR0B family.

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Generation of Two Distinct Functional Isoforms of Dosage-Sensitive Sex Reversal-Adrenal Hypoplasia Congenita-Critical Region on the X Chromosome Gene 1 (DAX-1) by Alternative Splicing

Cited by 38 publications

References 28 publications

Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis

Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis

DAX1: Increasing complexity in the roles of this novel nuclear receptor

LXXLL motifs and AF-2 domain mediate SHP (NR0B2) homodimerization and DAX1 (NR0B1)–DAX1A heterodimerization

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