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

Jacob, Anne L.; Lund, Johan; Martinez, Pedro; Hedin, Lars O.

doi:10.1074/jbc.m104427200

Cited by 78 publications

(65 citation statements)

References 55 publications

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“…We further postulated that activation of the cAMP signal transduction pathway led to a series of events that altered the conformation of SF1, thereby promoting disassociation of SPH and activation of the receptor. As mentioned previously, since phosphorylation (Hammer et al, 1999) and acetylation (Chen et al, 2005;Ishihara and Morohashi, 2005;Jacob et al, 2001) of SF1 are key for receptor activation, it is probable that the binding of SF1 to target genes involves one or more post-translational modifications. Additionally, based on the receptor's large ligand binding pocket (Li et al, 2005), it is also likely that cAMP promotes the exchange of SPH for an activating ligand.…”

Section: Sphingosine Is a Ligand For Sf1mentioning

confidence: 89%

“…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%

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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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Section: Sphingosine Is a Ligand For Sf1mentioning

confidence: 89%

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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“…SF1 plays an essential role in inducing the transcription of multiple steroidogenic genes, including cytochrome CYP17A1 in the adrenal cortex and gonads. The ability of SF1 to activate target genes is regulated by mechanisms including coregulatory proteins (60)(61)(62)(63), posttranslational modifi cation ( 27,28,(64)(65)(66)(67)(68), and ligand binding ( 25,(69)(70)(71)(72).…”

Section: Discussionmentioning

confidence: 99%

cAMP-stimulated transcription of DGKθ requires steroidogenic factor 1 and sterol regulatory element binding protein 1

Cai

Sewer

2013

Journal of Lipid Research

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( 4 ). DGK -null mice exhibit several neural abnormalities, including a higher resistance of electroconvulsive shock ( 5 ) and increased cyclooxygenase 2 and tyrosine hydroxylase expression ( 6 ), suggesting a role for DGK in regulating synaptic activity. Mice lacking DGK ␣ ( 7 ) or DGK ( 8 ) exhibit enhanced T cell function and demonstrate a role for these kinases in controlling DAG metabolism during the immune response. DGK isoforms have been implicated in various other cellular processes including inhibition of Rap1 signaling ( 9 ) and retinoblastoma-mediated cell cycle control ( 10 ). DGK is activated by nerve growth factor in PC12 cells ( 11 ) and thrombin in IIC9 fi broblasts ( 12, 13 ), whereas DGK promotes myogenesis in C2C12 cells ( 14 ) and DGK ␥ plays a role in regulating the cell cycle in CHO-K cells ( 15 ).To date, 10 mammalian DGKs have been identifi ed that are divided into fi ve groups based on functional domains ( 16,17 ). However, all isoforms contain cysteine-rich zinc fi nger-like structures, a conserved catalytic region ( 18-21 ). DGK , the sole member of group V, is comprised of three cysteine-rich domains (CRDs), a proline/glycine-rich domain at its N terminus, and a pleckstrin homology (PH) with an overlapping Ras-binding domain ( 22 ). While the functions of many of the other domains in DGK are unclear, the catalytic activity requires all domains of the enzyme ( 23 ). It has been postulated that the CRDs of the enzyme are required both for correct folding of the protein and for substrate presentation ( 23 ). Mutation of the CRD of DGK diminishes DAG-induced translocation of the enzyme to the plasma membrane ( 24 ); whereas the interaction between DGK and the nuclear receptor steroidogenic factor 1 (SF1) requires the PH domain ( 25 ). Abstract Diacylglycerol kinase (DGK) is

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“…These modifications typically involve the addition or removal of phosphate or acetyl groups, changes that can alter the ability of the target protein to bind DNA or recruit accessory/chaperone proteins. Recently, SF-1 has been shown to exhibit enhanced transcriptional activity upon acetylation (Jacob et al 2001). Transcription factors, such as CREB and steroid receptor co-activator-1, are known to interact with SF-1, and each has histone acetyltransferase activity.…”

Section: Post-translational Modification Of Sf-1mentioning

confidence: 99%

“…Transcription factors, such as CREB and steroid receptor co-activator-1, are known to interact with SF-1, and each has histone acetyltransferase activity. Inhibition of histone deacetytalases (using trichostatin A) enhances the effects of SF-1 on target gene transcription (Jacob et al 2001) and stabilises SF-1 protein.…”

Section: Post-translational Modification Of Sf-1mentioning

confidence: 99%