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Regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 by protein kinase Cδ-mediated phosphorylation

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Abstract

Cyclin-dependent kinase (CDK) inhibitor p21WAF1/CIP1(-/-)-null mice have an increased incidence of tumor formation. Here, we demonstrate that p21WAF1/CIP1 is unstable in HeLa cells treated with siRNA duplexes that target PKCδ. PKCδ phosphorylates p21WAF1/CIP1 at a serine residue (146Ser) located in its C-terminal domain. In cells treated with 12-O-tetradecanoylphorbol 13-acetate, the levels of both p21WAF1/CIP1 and its 146Ser-phosphorylated form increased significantly. We also show that a substitution, resulting from a single nucleotide polymorphism (SNP) at 149Asp found in certain cancer patients, strongly compromises PKCδ-mediated phosphorylation at 146Ser and results in cells that are relatively resistant to TNFα-induced apoptosis. Thus, post-translational phosphorylation of p21WAF1/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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Abbreviations

PKC:

Protein kinase C

TPA:

12-O-tetradecanoylphorbol 13-acetate

CDK:

Cyclin-dependent kinase

SNP:

Single nucleotide polymorphism

siRNA:

Small interfering RNA

CHX:

Cycloheximide

PSI:

Proteasome inhibitor

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Acknowledgements

This work was supported by a grant from the National Research Laboratory Fund (M10104000129-02J0000-05910) from the Ministry of Science and Technology, Korea, to S. K. L.

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Authors and Affiliations

  1. Division of Pharmaceutical Biosciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea

    You-Take Oh, Kwang Hoon Chun, Byoung Duck Park, Joon-Seok Choi & Seung Ki Lee

  2. The Research Institute for Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea

    You-Take Oh, Kwang Hoon Chun, Byoung Duck Park, Joon-Seok Choi & Seung Ki Lee

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  1. You-Take Oh
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Correspondence to Seung Ki Lee.

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Oh, YT., Chun, K.H., Park, B.D. et al. Regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 by protein kinase Cδ-mediated phosphorylation . Apoptosis 12, 1339–1347 (2007). https://doi.org/10.1007/s10495-007-0066-8

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