Title

p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene

UMMS Affiliation

Program in Molecular Medicine

Publication Date

2014-08-01

Document Type

Article

Subjects

Animals; Bucladesine; Cell Line; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; HEK293 Cells; Humans; Isoenzymes; MAP Kinase Kinase 3; MAP Kinase Kinase 6; Mice; Mice, Knockout; Oxidants; Phosphoproteins; Progesterone; Promoter Regions, Genetic; RNA, Messenger; Rats; Steroids; Transcription, Genetic; p38 Mitogen-Activated Protein Kinases

Disciplines

Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology

Abstract

STAR/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.

Keywords

CREB, MLTC-1 cells, Y1 cells, cAMP, oxidative stress, steroid hormones, steroids

DOI of Published Version

10.1530/JME-13-0287

Source

J 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

Journal/Book/Conference Title

Journal of molecular endocrinology

Related Resources

Link to Article in PubMed

PubMed ID

24780837

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