Methylosome protein 50 and PKC{delta}/p38{delta} signaling control keratinocyte proliferation via opposing effects on p21Cip1 gene expression [Gene Regulation]

April 7th, 2015 by Saha, K., Eckert, R. L.

Protein arginine methyltransferase 5 (PRMT5) is a key epigenetic regulator the symmetrically dimethylates arginine residues on histone H3 and H4 to silence gene expression. PRMT5 is frequently observed in a complex with the cofactor, methylosome protein 50 (MEP50), which is required for PRMT5 activity. PKCδ/p38δ signaling, a key controller of keratinocyte proliferation and differentiation, increases p21Cip1 expression to suppress keratinocyte proliferation. We now show that MEP50 enhances keratinocyte proliferation and survival via mechanisms that include silencing of p21Cip1 expression. This is associated with enhanced PRMT5/MEP50 interaction at the p21Cip1 promoter and enhanced arginine dimethylation of promoter-associated histones H3 and H4. It is also associated with a MEP50-dependent reduction in the level of p53, a key controller of p21Cip1 gene expression. We confirm an important biological role for MEP50 and PRMT5 in regulating keratinocyte proliferation using a stratified epidermal equivalent model that mimics in vivo epidermal keratinocyte differentiation. In this model, PRMT5 or MEP50 knockdown results in reduced keratinocyte proliferation. We further show that PKCδ/p38δ signaling suppresses MEP50 expression leading to reduced H3/H4 arginine dimethylation at the p21Cip1 promoter, and that this is associated with enhanced p21Cip1 expression and reduced cell proliferation. These findings describe an opposing action between PKCδ/p38δ MAPK signaling and PRMT5/MEP50 epigenetic silencing mechanisms in regulating cell proliferation.
  • Posted in Journal of Biological Chemistry, Publications
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