p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene
Program in Molecular Medicine
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
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
CREB, MLTC-1 cells, Y1 cells, cAMP, oxidative stress, steroid hormones, steroids
DOI of Published Version
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 of molecular endocrinology
Zaidi, Syed Kashif; Shen, Wen-Jun; Bittner, Stefanie; Bittner, Alex; McLean, Mark P.; Han, Jiahuai; Davis, Roger J.; Kraemer, Fredric B.; and Azhar, Salman, "p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene" (2014). Davis Lab Publications. 9.