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  • Title: Novel protein kinase C-epsilon inhibits human CYP11B2 gene expression through ERK1/2 signalling pathway and JunB.
    Author: LeHoux JG, Lefebvre A.
    Journal: J Mol Endocrinol; 2006 Feb; 36(1):51-64. PubMed ID: 16461926.
    Abstract:
    We previously reported that H295R cells co-express three diacylglycerol (DAG)-dependent protein kinase Cs (PKCs), namely conventional (c) PKCalpha and novel (n) PKCepsilon and PKCtheta. The aim of the present work was to evaluate the implication of DAG-dependent PKCs in the activation of p44/42 MAP kinase (MAPK) by angiotensin II (Ang II) and to define the role of this pathway towards CYP11B2 regulation in H295R cells. The PKC inhibitor bisindolylmaleimide 1 (Bis) inhibited Ang II-induced p44/42 MAPK phosphorylation whereas the cPKC inhibitor Gö6976 failed to do so, thus ruling out the participation of PKCalpha. Ang II activated nPKCepsilon and did not affect nPKCtheta, pinpointing PKCepsilon as the mediator of Ang II in p44/42 MAPK activation. Overexpression of wild-type ERK1 and ERK2 significantly reduced basal as well as Ang II-stimulated human -2023CYP11B2-CAT activity; conversely, the two dominant negative mutants increased them. Overexpression of constitutively active (ca) PKCsuppressed Ang II-induced -2023CYP11B2-CAT activity. Infection of H295R cells with adenoviruses (Adv) expressing caPKCepsilon activated endogenous MEK1/2 and p44/42 MAPK. Adv-caPKCepsilon inhibited Ang II-stimulated aldosterone synthase mRNA levels and this action was reversed by the MEK1 inhibitor, PD98059. Also, Ang II increased JunB protein levels and this effect was inhibited by PD98059 and Bis. Adv-caPKCepsilon enhanced JunB protein levels and PD98059 attenuated the increase. JunB overexpression abolished the Ang II-induced promoter activity within -138 bp of the 5'-flanking region of CYP11B2. Collectively, these results demonstrate that PKCepsilon inhibits CYP11B2 transcription through the p44/42 MAPK pathway and JunB in H295R cells.
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