Transcriptional repression of the rat steroidogenic acute regulatory (StAR) protein gene by the AP-1 family member c-Fos

Shea-Eaton, Wendy; Sandhoff, Todd W.; Lopez, Dayami; Hales, Dale B.; McLean, Mark

doi:10.1016/s0303-7207(01)00715-8

Cited by 81 publications

(52 citation statements)

References 36 publications

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“…The CRE2 site is also analogous to an activator protein 1 (AP-1) sequence (TGACTGA) and, as such, a role for AP-1 in StAR gene expression cannot be eliminated. Indeed, the AP-1 family, composed of Jun and Fos oncoproteins, was found to be involved in decreasing cAMP mediated StAR gene expression in MA-10 cells (PR Manna, DW Eubank and DM Stocco unpublished data), an observation consistent with recent findings (Manna et al 2002b, Shea-Eaton et al 2002.…”

Section: Discussionsupporting

confidence: 85%

Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1

Pr¹,

Eubank²,

Lalli³

et al. 2003

Journal of Molecular Endocrinology

114

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Transcriptional induction by cAMP is mediated through the interaction of the cAMP response-element binding protein (CREB) with a cAMP response element (CRE) in the promoter of target genes. The steroidogenic acute regulatory (StAR) protein gene is regulated by cAMP-mediated signaling in steroidogenic cells even though its promoter lacks a consensus CRE. Previously, we have identified three highly conserved 5′-CRE half-sites within the -96/-67 bp region of the mouse StAR gene, and a member of the CREB family (CREB/CRE modulator (CREM)) was shown to be involved in its expression and regulation. Here we show that CREB and CREMτ (but not CREMα and CREMβ) have qualitatively similar effects on StAR promoter activity in response to (Bu) 2 cAMP. Studies on the effects of the functional integrity of the CRE half-sites on CREB-dependent (Bu) 2 cAMP-mediated StAR gene transcription demonstrated the greater importance of the CRE2 site in comparison with the CRE1 and CRE3 sites. The CRE2 sequence was also found to bind specifically to recombinant CREB protein and nuclear extract from MA-10 mouse Leydig tumor cells. The cAMP and CREB/CREM responsive region (-151/-1 bp) of the mouse StAR promoter also contains three recognition motifs for steroidogenic factor 1 (SF-1). Electrophoretic mobility shift assays and reporter gene analyses demonstrated the involvement of different SF-1 elements in StAR gene expression with the order of importance being SF-1/3>SF-1/1>SF-1/2. Specific mutations that eliminated the binding sites of CRE and SF-1 elements, either alone or in combination, resulted in an attenuation of StAR promoter activity, indicating that CREB and SF-1 can regulate StAR gene transcription in a cooperative fashion. In addition, mammalian two-hybrid assays revealed a high affinity protein-protein interaction between CREB/CREMτ and SF-1 which appeared to be dependent upon CREB protein phosphorylation. These findings further demonstrate CREB's role in StAR gene transcription and also provide evidence that the combined action of CREB/CREMτ and SF-1 results in enhanced activation of the StAR promoter.

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Section: Discussionsupporting

confidence: 85%

Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1

Pr¹,

Eubank²,

Lalli³

et al. 2003

Journal of Molecular Endocrinology

114

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“…We cannot rule out the possibility that GX sPLA 2 exerts an effect on StAR promoter activity through alternative pathways in addition to suppression of LXR-mediated StAR activation. Earlier studies have shown that AA metabolites generated by COX-2 inhibit steroidogenesis (37), and prostaglandin F2␣ negatively regulates corticosteroid production by inhibiting StAR gene expression through the AP-1 family member c-Fos (38). Contrary to these reports, certain other studies indicate AA can activate steroidogenesis (39) through the generation of 15-lipoxygenase-derived metabolite(s) (40).…”

Section: Discussionmentioning

confidence: 98%

Group X Secretory Phospholipase A2 Regulates the Expression of Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenal Glands

Shridas

Bailey

Boyanovsky

et al. 2010

Journal of Biological Chemistry

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We developed C57BL/6 mice with targeted deletion of group X secretory phospholipase A 2 (GX KO). These mice have ϳ80% higher plasma corticosterone concentrations compared with wild-type (WT) mice under both basal and adrenocorticotropic hormone (ACTH)-induced stress conditions. This increased corticosterone level was not associated with increased circulating ACTH or a defect in the hypothalamic-pituitary axis as evidenced by a normal response to dexamethasone challenge. Primary cultures of adrenal cells from GX KO mice exhibited significantly increased corticosteroid secretion compared with WT cells. Conversely, overexpression of GX secretory phospholipase A 2 (sPLA 2 ), but not a catalytically inactive mutant form of GX sPLA 2 , significantly reduced steroid production 30 -40% in Y1 mouse adrenal cell line. This effect was reversed by the sPLA 2 inhibitor, indoxam. Silencing of endogenous M-type receptor expression did not restore steroid production in GX sPLA 2 -overexpressing Y1 cells, ruling out a role for this sPLA 2 receptor in this regulatory process. Expression of steroidogenic acute regulatory protein (StAR), the rate-limiting protein in corticosteroid production, was ϳ2-fold higher in adrenal glands of GX KO mice compared with WT mice, whereas StAR expression was suppressed in Y1 cells overexpressing GX sPLA 2 . Results from StAR-promoter luciferase reporter gene assays indicated that GX sPLA 2 antagonizes StAR promoter activity and liver X receptor-mediated StAR promoter activation. In summary, GX sPLA 2 is expressed in mouse adrenal glands and functions to negatively regulate corticosteroid synthesis, most likely by negatively regulating StAR expression.

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“…3). Residual c-JUN-dependent activation of the Star promoter constructs containing a mutated AP-1 element at K 78 bp might be attributed to the presence of other functional AP-1 elements within the K902 bp Star promoter fragment (Shea-Eaton et al 2002). Therefore, the additive effect of NUR77/c-JUN requires an intact binding site for one of the factors.…”

Section: Ma-10 Leydig Cells Have Been Shown To Express C-jun and C-fomentioning

confidence: 99%

The nuclear receptors NUR77 and SF1 play additive roles with c-JUN through distinct elements on the mouse Star promoter

Martin¹,

Tremblay²

2008

Journal of Molecular Endocrinology

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The steroidogenic acute regulatory protein plays an essential role in steroid biosynthesis in steroidogenic cells. It is involved in the transport of cholesterol through the mitochondrial membrane where the first step of steroidogenesis occurs. Star gene expression in testicular Leydig cells is regulated by the pituitary LH through the cAMP signaling pathway. So far, several transcription factors have been implicated in the regulation of Star promoter activity in these cells. These include the nuclear receptors NUR77 and SF1, AP-1 family members (particularly c-JUN), GATA4, C/EBPb, DLX5/6, and CREB. Some of these factors were also shown to act in a cooperative manner to further enhance Star promoter activity. Here, we report that NUR77 and c-JUN have additive effects on the Star promoter. These effects were abolished only when both elements, NUR77 at K95 bp and AP-1 at K78 bp, were mutated. Consistent with this, in vitro co-immunoprecipitation revealed that NUR77 and c-JUN interact and that this interaction is mediated through part of the ligand binding domain of NUR77. Furthermore, we found that SF1 could cooperate with c-JUN on the mouse Star promoter but this cooperation involved different regulatory elements. Collectively, our data not only provide new insights into the molecular mechanisms that control mouse Star transcription in Leydig cells but also reveal a novel mechanism for the regulation of NR4A1-dependent genes in tissues where NUR77 and c-JUN factors are co-expressed.

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Transcriptional repression of the rat steroidogenic acute regulatory (StAR) protein gene by the AP-1 family member c-Fos

Cited by 81 publications

References 36 publications

Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1

Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1

Group X Secretory Phospholipase A2 Regulates the Expression of Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenal Glands

The nuclear receptors NUR77 and SF1 play additive roles with c-JUN through distinct elements on the mouse Star promoter

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