SF-1 (Nuclear Receptor 5A1) Activity Is Activated by Cyclic AMP via p300-Mediated Recruitment to Active Foci, Acetylation, and Increased DNA Binding

Institute of Molecular Biology, 48, Academia Sinica, Nankang, Taipei 115, Taiwan.
Molecular and Cellular Biology (Impact Factor: 4.78). 01/2006; 25(23):10442-53. DOI: 10.1128/MCB.25.23.10442-10453.2005
Source: PubMed


Steroidogenic factor 1 (SF-1) is a nuclear receptor essential for steroidogenic gene expression, but how its activity is regulated
is unclear. Here we demonstrate that p300 plays an important role in regulating SF-1 function. SF-1 was acetylated in vitro
and in vivo by p300 at the KQQKK motif in the Ftz-F1 (Fushi-tarazu factor 1) box adjacent to its DNA-binding domain. Mutation
of the KQQKK motif reduced the DNA-binding activity and p300-dependent activation of SF-1. When stimulated with cyclic AMP
(cAMP), adrenocortical Y1 cells expressed more p300, leading to additional SF-1 association with p300 and increased SF-1 acetylation
and DNA binding. It also increased SF-1 colocalization with p300 in nuclear foci. Collectively, these results indicate that
SF-1 transcriptional activity is regulated by p300 in response to the cAMP signaling pathway by way of increased acetylation,
DNA binding, and recruitment to nuclear foci.

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    • "As the acetyl transferase activity of p300 is not required for this translocation, SF-1 is probably recruited to these transcriptionally active loci as a result of physical interactions with its co-regulators, such as p300 or GCN5. Moreover, p300-mediated acetylation of SF-1 at the FTZ-F1 domain increases its binding to p300, suggesting that acetylation is involved in retaining SF-1 in the transcriptionally active foci and thus facilitating the transcription of target genes (Chen et al., 2005). Although the phosphorylation of SF-1 at Ser-203 is involved in transcriptional regulation, this modification has not been reported to change its subcellular localization (Hammer et al., 1999; Lewis et al., 2008). "
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    ABSTRACT: Steroidogenic factor 1 (SF-1, Ad4bp, NR5A1) is a nuclear receptor expressed mainly in the adrenals and gonads. It activates the transcription of genes in steroidogenesis, reproduction, and energy metabolism. In addition, it also regulates the growth and differentiation of adrenogonadal primodial cells. SF-1 resides in the nucleus and the centrosome. SF-1 moves dynamically in the nucleus, and SF-1 location and activity are dynamically regulated by post-translational modification. In the centrosome, SF-1 maintains genomic integrity by controlling centrosome homeostasis. SF-1 prevents centrosome amplification by restricting aberrant activation of centrosomal DNA-PK. Upon SF-1 removal, DNA-PK is activated and centrosomes are amplified. This leads to genomic instability and cell growth defects. These data indicate that SF-1 at both the nucleus and the centrosome contributes to cell growth control, but the mechanisms of SF-1 action in different locations are different.
    Full-text · Article · Dec 2012 · Molecular and Cellular Endocrinology
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    • "These findings are in agreement with predictions made in our previous study and show similarities to similar to that of ERα acetylation [8]. In contrast to the previous observation in which acetylation of NRs affects transcriptional activity, acetylation of SF-1 by p300 does not alter transactivation, but rather increases SF-1 DNA binding activity and enhances localization of SF-1 to p300 foci in response to cAMP-dependent signaling [19] "
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    ABSTRACT: Acetylation is an essential post-translational modification featuring an acetyl group that is covalently conjugated to a protein substrate. Histone acetylation was first proposed nearly half a century ago by Dr. Vincent Allfrey. Subsequent studies have shown that the acetylated core histones are often associated with transcriptionally active chromatin. Acetylation at lysine residues of histone tails neutralizes the positive charge, which decreases their binding ability to DNA and increases the accessibility of transcription factors and coactivators to the chromatin template. In addition to histones, a number of non-histone substrates are acetylated. Acetylation of non-histone proteins governs biological processes, such as cellular proliferation and survival, transcriptional activity, and intracellular trafficking. We demonstrated that acetylation of transcription factors can regulate cellular growth. Furthermore, we showed that nuclear receptors (NRs) are acetylated at a phylogenetically conserved motif. Since our initial observations with the estrogen and androgen receptors, more than a dozen NRs have been shown to function as substrates for acetyltransferases with diverse functional consequences. This review focuses on the acetylation of NRs and the effect of acetylation on NR function. We discuss the potential role of acetylation in disease initiation and progression with an emphasis on tumorigenesis.
    Preview · Article · Feb 2011 · The Journal of steroid biochemistry and molecular biology
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    • "Collectively, these results suggest that ATR may not directly interact with NR5A receptors, but instead activates three signaling pathways known to activate NR5A receptors, including phosphorylation of SF-1, generation of SF-1 ligands, and increased production of cAMP. All of these effects would be predicted to activate SF-1 further [40], [41], [42], [43]. "
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    ABSTRACT: Atrazine (ATR) remains a widely used broadleaf herbicide in the United States despite the fact that this s-chlorotriazine has been linked to reproductive abnormalities in fish and amphibians. Here, using zebrafish we report that environmentally relevant ATR concentrations elevated zcyp19a1 expression encoding aromatase (2.2 microg/L), and increased the ratio of female to male fish (22 microg/L). ATR selectively increased zcyp19a1, a known gene target of the nuclear receptor SF-1 (NR5A1), whereas zcyp19a2, which is estrogen responsive, remained unchanged. Remarkably, in mammalian cells ATR functions in a cell-specific manner to upregulate SF-1 targets and other genes critical for steroid synthesis and reproduction, including Cyp19A1, StAR, Cyp11A1, hCG, FSTL3, LHss, INHalpha, alphaGSU, and 11ss-HSD2. Our data appear to eliminate the possibility that ATR directly affects SF-1 DNA- or ligand-binding. Instead, we suggest that the stimulatory effects of ATR on the NR5A receptor subfamily (SF-1, LRH-1, and zff1d) are likely mediated by receptor phosphorylation, amplification of cAMP and PI3K signaling, and possibly an increase in the cAMP-responsive cellular kinase SGK-1, which is known to be upregulated in infertile women. Taken together, we propose that this pervasive and persistent environmental chemical alters hormone networks via convergence of NR5A activity and cAMP signaling, to potentially disrupt normal endocrine development and function in lower and higher vertebrates.
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