p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene
AuthorsZaidi, Syed Kashif
McLean, Mark P.
Davis, Roger J.
Kraemer, Fredric B.
UMass Chan AffiliationsProgram in Molecular Medicine
Document TypeJournal Article
Cyclic AMP Response Element-Binding Protein
MAP Kinase Kinase 3
MAP Kinase Kinase 6
Promoter Regions, Genetic
p38 Mitogen-Activated Protein Kinases
Cellular and Molecular Physiology
MetadataShow full item record
AbstractSTAR/StarD1, part of a protein complex, mediates the transport of cholesterol from the outer to inner mitochondrial membrane, which is the rate-limiting step for steroidogenesis, and where steroid hormone synthesis begins. Herein, we examined the role of oxidant-sensitive p38 MAPKs in the regulation of STAR gene transcription, using model steroidogenic cell lines. Our data indicate that oxidant activation of p38 MAPK exhibits a negative regulatory role in the induction of functional expression of STAR, as evidenced by enhanced induction of STAR (mRNA/protein) expression and increased steroidogenesis during pharmacological inhibition of p38 MAPK or in cells with increased transient overexpression of a dominant-negative (dn) form of p38 MAPKalpha or p38 MAPKbeta. Studies with rat Star-promoter demonstrated that overexpression of p38 MAPKalpha-wt, -beta, or -gamma significantly reduced both basal and cAMP-sensitive promoter activity. In contrast, overexpression of p38 MAPKalpha-dn, -beta, or -gamma enhanced the Star promoter activity under basal conditions and in response to cAMP stimulation. Use of various constitutively active and dn constructs and designer knock-out cell lines demonstrated that MKK3 and MKK6, the upstream activators of p38 MAPKs, play a role in p38 MAPKalpha-mediated inhibition of Star promoter activity. In addition, our studies raised the possibility of CREB being a potential target of the p38 MAPK inhibitory effect on Star promoter activity. Collectively, these data provide novel mechanistic information about how oxidant-sensitive p38 MAPKs, particularly p38 MAPKalpha, contribute to the negative regulation of Star gene expression and inhibit steroidogenesis.
SourceJ Mol Endocrinol. 2014 Aug;53(1):1-16. doi: 10.1530/JME-13-0287. Epub 2014 Apr 29. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/28365
Related ResourcesLink to Article in PubMed
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