p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene
Authors
Zaidi, Syed KashifShen, Wen-Jun
Bittner, Stefanie
Bittner, Alex
McLean, Mark P.
Han, Jiahuai
Davis, Roger J.
Kraemer, Fredric B.
Azhar, Salman
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2014-08-01Keywords
AnimalsBucladesine
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
CREB
MLTC-1 cells
Y1 cells
cAMP
oxidative stress
steroid hormones
steroids
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Molecular Biology
Metadata
Show full item recordAbstract
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.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 siteDOI
10.1530/JME-13-0287Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28365PubMed ID
24780837Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1530/JME-13-0287
Scopus Count
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