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J Mol Endocrinol. 2014 Aug;53(1):1-16. doi: 10.1530/JME-13-0287. Epub 2014 Apr 29.

p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene.

Author information

1
Geriatric ResearchEducation and Clinical Center (GRECC-182B), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USADivision of EndocrinologyDivision of Gastroenterology and HepatologyStanford University, Stanford, California 94305, USADepartment of Obstetrics and GynecologyUniversity of South Florida College of Medicine, Tampa, Florida 33612, USAState Key Laboratory of Cellular Stress BiologySchool of Life Sciences, Xiamen University, Xiamen, Fujian 361005, ChinaProgram in Molecular MedicineUniversity of Massachusetts Medical School, Worcester, Massachusetts 01605, USAGeriatric ResearchEducation and Clinical Center (GRECC-182B), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USADivision of EndocrinologyDivision of Gastroenterology and HepatologyStanford University, Stanford, California 94305, USADepartment of Obstetrics and GynecologyUniversity of South Florida College of Medicine, Tampa, Florida 33612, USAState Key Laboratory of Cellular Stress BiologySchool of Life Sciences, Xiamen University, Xiamen, Fujian 361005, ChinaProgram in Molecular MedicineUniversity of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
2
Geriatric ResearchEducation and Clinical Center (GRECC-182B), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USADivision of EndocrinologyDivision of Gastroenterology and HepatologyStanford University, Stanford, California 94305, USADepartment of Obstetrics and GynecologyUniversity of South Florida College of Medicine, Tampa, Florida 33612, USAState Key Laboratory of Cellular Stress BiologySchool of Life Sciences, Xiamen University, Xiamen, Fujian 361005, ChinaProgram in Molecular MedicineUniversity of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
3
Geriatric ResearchEducation and Clinical Center (GRECC-182B), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USADivision of EndocrinologyDivision of Gastroenterology and HepatologyStanford University, Stanford, California 94305, USADepartment of Obstetrics and GynecologyUniversity of South Florida College of Medicine, Tampa, Florida 33612, USAState Key Laboratory of Cellular Stress BiologySchool of Life Sciences, Xiamen University, Xiamen, Fujian 361005, ChinaProgram in Molecular MedicineUniversity of Massachusetts Medical School, Worcester, Massachusetts 01605, USAGeriatric ResearchEducation and Clinical Center (GRECC-182B), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USADivision of EndocrinologyDivision of Gastroenterology and HepatologyStanford University, Stanford, California 94305, USADepartment of Obstetrics and GynecologyUniversity of South Florida College of Medicine, Tampa, Florida 33612, USAState Key Laboratory of Cellular Stress BiologySchool of Life Sciences, Xiamen University, Xiamen, Fujian 361005, ChinaProgram in Molecular MedicineUniversity of Massachusetts Medical School, Worcester, Massachusetts 01605, USA salman.azhar@va.gov.

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 MAPKα or p38 MAPKβ. Studies with rat Star-promoter demonstrated that overexpression of p38 MAPKα-wt, -β, or -γ significantly reduced both basal and cAMP-sensitive promoter activity. In contrast, overexpression of p38 MAPKα-dn, -β, or -γ 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 MAPKα-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 MAPKα, 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

PMID:
24780837
PMCID:
PMC4077990
DOI:
10.1530/JME-13-0287
[Indexed for MEDLINE]
Free PMC Article
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