p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene. Journal of molecular endocrinology Zaidi, S. K., Shen, W., Bittner, S., Bittner, A., McLean, M. P., Han, J., Davis, R. J., Kraemer, F. B., Azhar, S. 2014; 53 (1): 1-16

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 MAPKa or p38 MAPKß. Studies with rat Star-promoter demonstrated that overexpression of p38 MAPKa-wt, -ß, or -? significantly reduced both basal and cAMP-sensitive promoter activity. In contrast, overexpression of p38 MAPKa-dn, -ß, or -? 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 MAPKa-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 MAPKa, contribute to the negative regulation of Star gene expression and inhibit steroidogenesis.

View details for DOI 10.1530/JME-13-0287

View details for PubMedID 24780837