SUMO Modification of Repression Domains Modulates Function of Nuclear Receptor 5A1 (Steroidogenic Factor-1)

Chen, Wei Yi; Lee, Wen Chih; Hsu, Nai Chi; Huang, Fu; Chung, Bon Chu

doi:10.1074/jbc.m405006200

Cited by 91 publications

(91 citation statements)

References 31 publications

(34 reference statements)

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“…Fourth, it has been proposed that SUMO-1 conjugation targets proteins to different cellular localizations. SF-1 can be directed into nuclear speckles and sequestered from the nucleolus in the presence of SUMO-1, thus resulting in transcriptional repression (43). It is therefore important to investigate whether and how MR activity and subcellular localization are functionally linked for further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Considerable numbers of nuclear receptors, including glucocorticoid receptor (26 -30), androgen receptor (21,22,(31)(32)(33)(34)(35)(36), progesterone receptor (36,37), MR (38), estrogen receptor ␣ (39), peroxisome proliferator-activated receptor ␥ (40 -42), and SF-1 (43)(44)(45), are modified by SUMO through a series of enzyme reactions, and sumoylation of the receptors mostly resulted in repression of the receptor-dependent transcription. In this study, we focused on the protein-protein interaction between Ubc9 and MR. We describe a new function of Ubc9 as a coactivator of MR by formation of a complex with N-terminal MR and SRC-1 beyond the known SUMO E2-conjugating enzyme, although sumoylation of MR repressed the receptor-dependent transactivation.…”

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confidence: 99%

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Coactivation of the N-terminal Transactivation of Mineralocorticoid Receptor by Ubc9

Yokota

Shibata

Kurihara

et al. 2007

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Coactivation of the N-terminal Transactivation of Mineralocorticoid Receptor by Ubc9

Yokota

Shibata

Kurihara

et al. 2007

Journal of Biological Chemistry

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“…Although an oxysterol was reported to activate SF-1 (40), this finding could not be confirmed (41). Alternative modes of regulation for SF-1, including phosphorylation (42,43) and sumoylation (44), have been presented. A recent mouse LRH-1 (mLRH-1) structure revealed it to have a large empty pocket, but mutations made to fill this pocket did not reduce the transcriptional activity, which suggested that the activity of mLRH-1 may be ligand-independent (45).…”

mentioning

confidence: 83%

The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1

Wang¹,

Zhang²,

Marimuthu³

et al. 2005

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

132

134

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Steroidogenic factor-1 (SF-1) and liver receptor homologue-1 (LRH-1) belong to the fushi tarazu factor 1 subfamily of nuclear receptors. SF-1 is an essential factor for sex determination during development and regulates adrenal and gonadal steroidogenesis in the adult, whereas LRH-1 is a critical factor for development of endodermal tissues and regulates cholesterol and bile acid homeostasis. Regulatory ligands are unknown for SF-1 and LRH-1. A reported mouse LRH-1 structure revealed an empty pocket in a region commonly occupied by ligands in the structures of other nuclear receptors, and pocket-filling mutations did not alter the constitutive activity observed. Here we report the crystal structures of the putative ligand-binding domains of human SF-1 at 2.1-Å resolution and human LRH-1 at 2.5-Å resolution. Both structures bind a coactivator-derived peptide at the canonical activationfunction surface, thus adopting the transcriptionally activating conformation. In human LRH-1, coactivator peptide binding also occurs to a second site. We discovered in both structures a phospholipid molecule bound in a pocket of the putative ligand-binding domain. MS analysis of the protein samples used for crystallization indicated that the two proteins associate with a range of phospholipids. Mutations of the pocket-lining residues reduced the transcriptional activities of SF-1 and LRH-1 in mammalian cell transfection assays without affecting their expression levels. These results suggest that human SF-1 and LRH-1 may be ligand-binding receptors, although it remains to be seen if phospholipids or possibly other molecules regulate SF-1 or LRH-1 under physiological conditions.x-ray crystallography ͉ phospholipid ͉ nuclear receptor ͉ steroid ͉ bile S teroidogenic factor-1 (SF-1; AD4BP͞NR5A1) and liver receptor homologue-1 (LRH-1; CPF͞FTF͞NR5A2), expressed in man, are homologues of the fushi tarazu factor-1 of Drosophila (1) and FF1B of fish (2). Together, these factors constitute the NR5A subfamily of nuclear receptors (NRs) (3). SF-1 and LRH-1 function as monomers (4) to regulate genes by binding to similar response elements.SF-1 is expressed in the adrenal, testes, ovary, pituitary, hypothalamus, spleen, and skin and regulates genes that direct biosynthesis of adrenal and gonadal steroids as well as Mullerian hormone and gonadotropins (5, 6). SF-1 is essential for normal adrenal and gonadal development given that SF-1 knockout in mice causes adrenal and gonadal agenesis and impaired gonadotropin expression, resulting in postnatal death due to severe adrenal insufficiency (7,8). SF-1 knockout also causes abnormalities of the ventromedial hypothalamic nucleus, the control center for satiety and feeding, which suggests that SF-1 may have broader roles in the control of metabolism and obesity (9). In humans, partial loss-of-function mutations in SF-1 result in XY sex reversal and adrenal failure (10, 11). Although SF-1 is expressed in the ovary (12), a mutation of SF-1 was observed not to affect ovarian development; thus, SF-1 may no...

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“…Phosphorylation of serine-203 is key for coactivator binding and the transactivation potential of the receptor (Hammer et al, 1999). The ability of SF1 to activate target gene expression is also regulated by SOMUylation (Chen et al, 2004;Komatsu et al, 2004;Lee et al, 2005), acetylation (Chen et al, 2005;Ishihara and Morohashi, 2005;Jacob et al, 2001), and interaction with various coregulatory proteins (Chen et al, 2005).…”

Section: Regulation Of Sf1 Activitymentioning

confidence: 99%

Steroidogenic factor-1 is a sphingolipid binding protein

Urs

Dammer

Kelly

et al. 2007

Molecular and Cellular Endocrinology

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Steroidogenic factor (SF1, NR5A1, Ad4BP) is an orphan nuclear receptor that is essential for steroid hormone-biosynthesis and endocrine development. Studies have found that the ability of this receptor to increase target gene expression can be regulated by post-translational modification, subnuclear localization, and protein-protein interactions. Recent crystallographic studies and our mass spectrometric analyses of the endogenous receptor have demonstrated an integral role for ligandbinding in the control of SF1 transactivation activity. Herein, we discuss our findings that sphingosine is an endogenous ligand for SF1. These studies and the structural findings of others have demonstrated that the receptor can bind both sphingolipids and phospholipids. Thus, it is likely that multiple bioactive lipids are ligands for SF1 and that these lipids will differentially act to control SF1 activity in a context-dependent manner. Finally, these findings highlight a central role for bioactive lipids as mediators of trophic-hormone stimulated steroid hormone biosynthesis. Keywordssteroidogenic factor-1; CYP17; sphingosine; cAMP; adrenocorticotropin Regulation of SF1 activitySteroid hormone biosynthesis involves the concerted action of a group of proteins that regulate substrate delivery and metabolism. Both the activity and expression of these enzymes is controlled by the integration of signaling pathways. One of these signal transduction pathways involves the activation of the cAMP-dependent protein kinase (PKA). A consequence of PKA activation is increased transcription of steroidogenic genes. This increase in transcription is mediated by the binding of various transcription factors, including SF1, to cAMP responsive sequences in the promoters of steroidogenic genes (Sewer and Waterman, 2001;Sewer and Waterman, 2003). SF1 is a nuclear receptor that plays a key role not only in steroidogenesis (Bakke et al., 2001), but also in endocrine development and sex differentiation (Hammer et al., 2005;Parker et al., 2002).Many laboratories have carried out research to determine the mechanism by which SF1 activates steroidogenic gene transcription. Although transcription of steroidogenic genes Corresponding author: Marion B. Sewer, School of Biology, Georgia Institute of Technology, 310 Ferst Drive, Atlanta, Tel: (404) Fax: (404) 894-0519; E-mail: marion.sewer@biology.gatech.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Bioactive sphingolipids in steroidogenesisSphingolipids are a diverse family of amphiphatic molecules that are comprised of a long-chain ...

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SUMO Modification of Repression Domains Modulates Function of Nuclear Receptor 5A1 (Steroidogenic Factor-1)

Cited by 91 publications

References 31 publications

Coactivation of the N-terminal Transactivation of Mineralocorticoid Receptor by Ubc9

Coactivation of the N-terminal Transactivation of Mineralocorticoid Receptor by Ubc9

The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1

Steroidogenic factor-1 is a sphingolipid binding protein

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