p38{delta} Regulates p53 to Control p21Cip1 Expression in Human Epidermal Keratinocytes [Gene Regulation]

March 5th, 2014 by Saha, K., Adhikary, G., Kanade, S. S., Rorke, E. A., Eckert, R. L.

PKCδ suppresses keratinocyte proliferation via a mechanism that involves increased expression of p21Cip1. However, the signaling mechanism that mediates this regulation is not well understood. Our present studies suggest that PKCδ activates p38δ leading to increased p21Cip1 promoter activity and p21Cip1 mRNA/protein expression. We further show that exogenously expressed p38δ increases p21Cip1 mRNA and protein, and that p38δ knockdown or expression of dominantnegative p38δ attenuates this increase. Moreover, p53 is an intermediary in this regulation, as p38δ expression increases p53 mRNA, protein and promoter activity and p53 knockdown attenuates the activation. We demonstrate a direct interaction of p38δ with PKCδ and MEK3, and show that exogenous agents which suppress keratinocyte proliferation activate this pathway. We confirm the importance of this regulation using a stratified epidermal equivalent model, that mimics in vivo-like keratinocyte differentiation. In this model, PKCδ or p38δ knockdown results in reduced p53 and p21Cip1 level and enhanced cell proliferation. We propose that PKCδ activates a MEKK1/MEK3/p38δ MAPK cascade to increase p53 level and p53 drives p21Cip1 gene expression.