Crosstalk of CREB and Fos/Jun on a single cis-element: transcriptional repression of the steroidogenic acute regulatory protein gene

Abstract

Transcriptional regulation of the steroidogenic acute regulatory (StAR) protein gene by cAMP-dependent mechanisms occurs in the absence of a consensus cAMP-response element (CRE; TGACGTCA) and is mediated by several sequencespecific transcription factors. We previously identified three CRE-like sites (within the K151/K1 bp cAMP-responsive region of the mouse StAR gene), of which the CRE2 site overlaps with an activator protein-1 (AP-1) motif (TGACTGA, designated as CRE2/AP-1) that can bind both CRE and AP-1 DNA-binding proteins. The present studies were aimed at exploring the functional crosstalk between CREB (CRE-binding protein) and cFos/cJun (AP-1 family members) on the CRE2/AP-1 element and its role in regulating transcription of the StAR gene. Using MA-10 mouse Leydig tumor cells, we demonstrate that the CRE and AP-1 families of proteins interact with the CRE2/AP-1 sequence. CREB, cFos, and cJun proteins were found to bind to the CRE2/AP-1 motif but not the CRE1 and CRE3 sites. Treatment with the cAMP analog (Bu) 2 cAMP augmented phosphorylation of CREB (Ser

Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers

“…A role for coactivator redistribution or squelching has been previously suggested to explain transcriptional repression by NRs, but most of those studies were performed using transfection to overexpress receptors or coactivators and used reporter genes as readouts (Kamei et al 1996;Fronsdal et al 1998;Lee et al 2000;Li et al 2000;Kim et al 2001;Zhang and Teng 2001;Manna and Stocco 2007;He et al 2012;Pascual-Garcia et al 2013). This model gained further support recently with evidence that the endogenous coactivator NCOA3 is lost from sites of diminished DNase I hypersensitivity upon E2 hormone treatment in MCF-7 cells (He et al 2012).…”

“…Support for this coactivator competition model, often referred to as squelching, has been largely based on TF overexpression experiments in transfection systems (Gill and Ptashne 1988;Kelleher et al 1990; Kamei et al 1996;Fronsdal et al 1998;Lee et al 2000;Li et al 2000;Kim et al 2001;Zhang and Teng 2001;Manna and Stocco 2007;He et al 2012;Pascual-Garcia et al 2013), although a recent study demonstrated coactivator redistribution with endogenous factors and chromatin on a genome-wide scale in the context of E2-treated MCF-7 cells (He et al 2012).…”

Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway

“…The regulation of StAR protein is executed primarily at the transcription level (Manna et al 2003, 2004, Hiroi et al 2004, Clem & Clark 2006, Manna & Stocco 2007, but posttranscriptional (phosphorylation) modification of StAR also plays a significant role in its functional expression (Stocco & Clark 1996). Transcriptional regulations of StAR have been extensively studied, and a cluster of transcription factors is involved in the regulatory process (Manna et al 2003, 2004, Hiroi et al 2004, Clem & Clark 2006, Manna & Stocco 2007. One of these transcription factors is AP-1, a dimeric complex composed primarily of the Fos and Jun family of proteins (Chinenov & Kerppola 2001, Hess et al 2004, which play a critical role in the regulation of StAR gene transcription (Manna et al 2004).…”

“…One of these transcription factors is AP-1, a dimeric complex composed primarily of the Fos and Jun family of proteins (Chinenov & Kerppola 2001, Hess et al 2004, which play a critical role in the regulation of StAR gene transcription (Manna et al 2004). Since CRE2 site overlaps with AP-1 site in the proximal StAR promoter region, its activity is also subject to regulation via the crosstalk between CREB and Fos/Jun proteins (Manna et al 2004, Manna & Stocco 2007. Interestingly, studies on the transcriptional regulation of another cholesterol transport protein, PBR/TSPO (which is believed to work in concert with StAR (Miller 2007), have also identified an AP-1 binding site in its proximal promoter region (Giatzakis et al 2007).…”

Regulation of the Glutathione S-Transferase P1 Expression in Melanoma Cells

“…Thus in one type of cells CRE acts as a positive element interacting with CREB and in the other type of cells as a negative element directly interacting with Fos in complex with ER . The similar phenomenon has been described for the gene encoding steroidogenic acute regulatory protein, which is up-regulated by CREB and down-regulated by Fos/Jun both interacting with CRE site (Manna & Stocco, 2007). The role of ER in regulation of GSTP1 expression was a disputable question until now.…”