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
PubMed ID
24780837
Repository Citation
Zaidi SK, Shen W, Bittner S, Bittner A, McLean MP, Han J, Davis RJ, Kraemer FB, Azhar S. (2014). p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene. Davis Lab Publications. https://doi.org/10.1530/JME-13-0287. Retrieved from https://escholarship.umassmed.edu/davis/9