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This Article Accepted manuscript (PDF) All Versions of this Article: JME-08-0077v1 41/5/329    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Manna, P. Articles by Stocco, D. PubMed PubMed Citation Articles by Manna, P. Articles by Stocco, D.

P Manna, Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, 79430, United States
D Stocco, Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, United States

Correspondence: Pulak Manna, Email: pulak.manna{at}ttuhsc.edu

Abstract

Activator protein 1 (AP-1) transcription factors (Jun and Fos) play critical roles in a wide variety of signaling processes including those in the PKC pathway, a pathway that is instrumental in the expression of the StAR protein. In the present study, we determined the functional involvement of one of the key AP-1 family members, c-Jun, in the regulation of PKC dependent StAR expression and steroidogenesis. MA-10 mouse Leydig tumor cells treated with an activator of PKC, PMA, demonstrated increases in the expression of the StAR and CYP11A1 proteins and progesterone synthesis, which coincided with the expression and phosphorylation of c-Jun (P-c-Jun). PMA was also capable of enhancing the cAMP analog, (Bu)2cAMP, stimulated c-Jun, StAR, P-StAR and progesterone levels. The induction of c-Jun mRNA expression and steroid synthesis by PMA requires de novo protein synthesis. ChIP studies revealed the association of P-c-Jun with the StAR proximal promoter and that PMA specifically enhanced in vivo P-c-Jun-DNA interaction. EMSA and reporter gene analyses demonstrated that c-Jun binds to the AP-1 motif (-81/-75 bp) in the StAR promoter, and that AP-1-DNA binding activity was highly correlated with the induction of c-Jun by PKC signaling. Overexpression of c-Jun increased the PMA-mediated transcription of the StAR gene, an event markedly decreased by TAM-67. Targeted silencing of endogenous c-Jun, by small interfering RNA, was correlated with the repression of basal- and PMA-mediated StAR expression and progesterone synthesis. These findings describe the mechanisms by which c-Jun influences PKC signaling and provide additional and novel insight into the regulation of the steroidogenic machinery in mouse Leydig cells.