title: Methylosome Protein 50 and PKCδ/p38δ Protein Signaling Control Keratinocyte Proliferation via Opposing Effects on p21Cip1 Gene Expression.
abstract: Protein arginine methyltransferase 5 (PRMT5) is a key epigenetic regulator that symmetrically dimethylates arginine residues on histones 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 p21(Cip1) expression to suppress keratinocyte proliferation. We now show that MEP50 enhances keratinocyte proliferation and survival via mechanisms that include silencing of p21(Cip1) expression. This is associated with enhanced PRMT5-MEP50 interaction at the p21(Cip1) promoter and enhanced arginine dimethylation of the promoter-associated histones H3 and H4. It is also associated with a MEP50-dependent reduction in the level of p53, a key controller of p21(Cip1) 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 p21(Cip1) promoter, and that this is associated with enhanced p21(Cip1) 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.
authors: From the Departments of Biochemistry and Molecular Biology.
authors: Kamalika
authors: K
authors: Saha
authors: From the Departments of Biochemistry and Molecular Biology, Dermatology, and Obstetrics and Gynecology and the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201 reckert@umaryland.edu.
authors: Richard L
authors: RL
authors: Eckert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D007124:Immunoenzyme Techniques; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050759:Cyclin-Dependent Kinase Inhibitor p21; D048308:Mitogen-Activated Protein Kinase 14; D051745:Protein Kinase C-delta; D011484:Protein-Arginine N-Methyltransferases; D012333:RNA, Messenger; C493956:CDKN1A protein, human; C400529:PRMT5 protein, human; C478359:WDR77 protein, human; D014157:Transcription Factors
keywords: cancer; cell cycle; cyclin; p38 MAPK; protein arginine N-methyltransferase 5 (PRMT5); protein kinase C (PKC)