The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus.

Steroidogenic factor 1 (SF-1) is a transcription factor belonging to the nuclear receptor superfamily. SF-1 regulates the expression of many genes involved in reproduction, steroidogenesis, and sexual differentiation. An important SF-1 target for male sexual differentiation is the gene encoding the Mü llerian-inhibiting substance hormone that induces regression of the Mü llerian ducts in the developing male embryo. Not long ago, a mutation (G35E) in the human SF-1 gene was identified as the cause of sex reversal and adrenal failure in a phenotypically female but genotypically XY individual. This suggested that the mutated SF-1 protein might interfere with the expression of SF-1 target gene(s) involved in the male sexual differentiation pathway, such as MIS. Surprisingly, the initial biochemical characterization of the SF-1 G35E mutant revealed that it could bind and activate the MIS promoter as efficiently as wild-type SF-1. MIS expression, however, does not rely solely on SF-1 but rather requires the concerted action of several transcription factors including GATA-4. We have previously reported that GATA-4 and SF-1 transcriptionally cooperate to synergistically activate the MIS promoter. Thus, we hypothesized that the phenotype observed with the SF-1 G35E mutation could be explained, at least in part, by a failure and/or a disruption of GATA-4/SF-1 synergism. We found that the SF-1 G35E mutant failed to synergize with GATA-4 despite a direct physical interaction between the two proteins. Interestingly, the SF-1 G35E mutant also disrupted transcriptional synergism between wild-type SF-1 and GATA-4, indicating that it could act as a dominant negative competitor. Thus, our results strengthen the importance of a GATA-4/SF-1 cooperation for MIS transcription and reveal that disruption of this synergism might be responsible for some cases of abnormal sex differentiation in humans.

mentioning

confidence: 59%

A Mutated Form of Steroidogenic Factor 1 (SF-1 G35E) That Causes Sex Reversal in Humans Fails to Synergize with Transcription Factor GATA-4

Tremblay¹,

Viger

2003

“…GST fusion proteins were incubated with an equal amount of immunoprecipitated GCN5 in the presence of 2 l of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]acetyl-CoA (59 mCi/mmol, Amersham Pharmacia Biotech) for 2 h at 37°C. Proteins were solubilized with SDS-PAGE sample buffer and resolved on 10% SDS-PAGE.…”

Section: Methodsmentioning

confidence: 99%

“…The SF-1 binding site in the Mullerian-inhibiting substance promoter, a key hormone involved in male sex differentiation, is required for the maintenance of Mullerian-inhibiting substance expression (10). Disruption of the SF-1 gene in mice leads to the complete agenesis of the adrenals and gonads and to abnormalities in the ventromedial hypothalamus (11,12). A mutation in the human gene encoding for SF-1 (FTZF1; fushi tarazu-related factor 1) has been described in a phenotypically female patient exhibiting primary adrenal failure and XY sex reversal (13).…”

mentioning

confidence: 99%

Acetylation of Steroidogenic Factor 1 Protein Regulates Its Transcriptional Activity and Recruits the Coactivator GCN5

Jacob

Lund

Martinez

et al. 2001

In this study we demonstrate that SF-1 is acetylated in vivo. Histone acetyltransferase GCN5 acetylates SF-1 in vitro. Moreover, we found that SF-1 recruited a novel coactivator GCN5, which can be a newly identified coactivator for SF-1. Acetylation of SF-1 stimulates its transcriptional activity. Inhibition of deacetylation by trichostatin A, a histone deacetylase inhibitor, increased SF-1-mediated transactivation and stabilized and induced the nuclear export of the SF-1 protein.

“…The functions of the orphans are less well understood, although it is thought that they have crucial roles in a variety of processes. Thus, the profound effects of the knock out of the SF-1/FTZ-F1 (8,9) or HNF-4 (10) genes demonstrate that both have essential developmental functions. The remarkable conservation of the Coup-TFs and other orphans in mammalian and non-mammalian species (11) provides a somewhat less direct, but compelling argument for an important role.…”

mentioning

confidence: 99%

Differential Transactivation by Two Isoforms of the Orphan Nuclear Hormone Receptor CAR

Choi¹,

Chung²,

Tzameli³

et al. 1997

258

193

We have identified a new murine orphan member of the nuclear hormone receptor superfamily, termed mCAR, that is closely related to the previously described human orphan MB67, referred to here as hCAR. Like hCAR, mCAR expression is highest in liver. In addition to the most abundant mCAR1 isoform, the mCAR gene expresses a truncated mCAR2 variant that is missing the C-terminal portion of the ligand binding/dimerization domain. The mCAR gene has 8 introns, and this mCAR2 variant is generated by a splicing event that skips the 8th exon. mCAR1, like hCAR, binds as a heterodimer with the retinoid X receptor to the retinoic acid response element from the promoter of the retinoic acid receptor ␤2 isoform. Consistent with its lack of a critical heterodimerization interface, the mCAR2 variant does not bind this site. Both mCAR1 and hCAR are apparently constitutive transcriptional activators. This activity is dependent on the presence of the conserved C-terminal AF-2 transcriptional activation motif. As expected from its inability to bind DNA, the mCAR2 variant neither transactivates by itself nor inhibits transactivation by hCAR or mCAR1.The nuclear hormone receptor superfamily includes the receptors for a number of potent biological regulators, such as steroids, retinoids, and thyroid hormone. With the recent addition of nuclear prostaglandin receptors (1, 2), and an oxysterol receptor (3), there are now more than 15 genes in mammalian genomes that encode such conventional receptors. An even larger set of genes encodes the orphan receptors, which are related to the conventional receptors but do not have known ligands. Particularly since individual genes for superfamily members frequently encode more than one isoform as a consequence of either alternative promoter utilization or alternative mRNA splicing, the total number of proteins that belong to the nuclear receptor superfamily is large.