Regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 by protein kinase Cdelta-mediated phosphorylation.
Cyclin-dependent kinase (CDK) inhibitor p21(WAF1/CIP1(-/-))-null mice have an increased incidence of tumor formation. Here, we demonstrate that p21(WAF1/CIP1) is unstable in HeLa cells treated with siRNA duplexes that target PKCdelta. PKCdelta phosphorylates p21(WAF1/CIP1 )at a serine residue ((146)Ser) located in its C-terminal domain. In cells treated with 12-O-tetradecanoylphorbol 13-acetate, the levels of both p21(WAF1/CIP1) and its (146)Ser-phosphorylated form increased significantly. We also show that a substitution, resulting from a single nucleotide polymorphism (SNP) at (149)Asp found in certain cancer patients, strongly compromises PKCdelta-mediated phosphorylation at (146)Ser and results in cells that are relatively resistant to TNFalpha-induced apoptosis. Thus, post-translational phosphorylation of p21(WAF1/CIP1) is important from an apoptotic cell death, and may also have patho-physiological relevance for the development of human cancer.
Oh
You-Take
YT
Division of Pharmaceutical Biosciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea.
Chun
Kwang Hoon
KH
Park
Byoung Duck
BD
Choi
Joon-Seok
JS
Lee
Seung Ki
SK
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D014409:Tumor Necrosis Factor-alpha; D051745:Protein Kinase C-delta; D053148:Caspase 3