p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene.
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.
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.
Syed Kashif
SK
Zaidi
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.
Wen-Jun
WJ
Shen
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.
Stefanie
S
Bittner
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.
Alex
A
Bittner
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.
Mark P
MP
McLean
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.
Jiahuai
J
Han
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.
Roger J
RJ
Davis
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.
Fredric B
FB
Kraemer
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.
Salman
S
Azhar
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016877:Oxidants / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics*; D011374:Progesterone / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013256:Steroids / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007527:Isoenzymes; D016877:Oxidants; D010750:Phosphoproteins; D012333:RNA, Messenger; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D003994:Bucladesine; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse
CREB; MLTC-1 cells; Y1 cells; cAMP; oxidative stress; steroid hormones; steroids