Journal
APOPTOSIS
Volume 12, Issue 7, Pages 1339-1347Publisher
SPRINGER
DOI: 10.1007/s10495-007-0066-8
Keywords
p21(WAF1/CIP1); phosphorylation; PKC delta; PKC alpha; TNF alpha
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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 PKC delta. PKC delta 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 PKC delta-mediated phosphorylation at (146)Ser and results in cells that are relatively resistant to TNF alpha-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.
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