p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bucladesine / pharmacology
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • HEK293 Cells
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • MAP Kinase Kinase 3 / deficiency
  • MAP Kinase Kinase 3 / genetics
  • MAP Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase 6 / deficiency
  • MAP Kinase Kinase 6 / genetics
  • MAP Kinase Kinase 6 / metabolism
  • Mice
  • Mice, Knockout
  • Oxidants / pharmacology
  • Phosphoproteins / genetics*
  • Progesterone / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Steroids / biosynthesis*
  • Transcription, Genetic / drug effects
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Isoenzymes
  • Oxidants
  • Phosphoproteins
  • RNA, Messenger
  • Steroids
  • steroidogenic acute regulatory protein
  • Progesterone
  • Bucladesine
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • Map2k3 protein, mouse
  • Map2k6 protein, mouse