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Brief Report

p21 (CDKN1A) is a Negative Regulator of p53 Stability

Eugenia V. Broude, Zoya N. Demidenko, Claire Vivo, Mari E. Swift, Brian M. Davis, Mikhail V. Blagosklonny and Igor B. Roninson

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Cell cycle arrest in response to DNA damage involves protein stabilization and consequent upregulation of p53, which induces transcription of cyclin-dependent kinase inhibitor p21 (CDKN1A). We now show that p21 acts as a negative regulator of the cellular levels of p53. p21 knockdown by short hairpin RNA strongly increased p53 upregulation by a DNA-damaging drug doxorubicin in HT1080 fibrosarcoma cells. A protease inhibitor N-Ac-Leu-Leu-norleucinal (ALLN) drastically increased the amount of p53 in HCT116 colon carcinoma cells, but it had no effect on the already high p53 level in a p21-/- derivative of this cell line. Inhibition of transcription, which increases p53 levels in different cell lines due to the degradation of p53-destabilizing proteins such as Mdm2, failed to increase but instead decreased the amount of p53 in p21-/- cells, despite a drastic decrease in the level of Mdm2. These results indicate that p21 acts as a negative regulator of p53 stability in different cell types. p53 regulation by p21 may provide a negative regulatory loop that limits p53 induction.

Authors

Eugenia V. Broude

Ordway Research Institute, Albany, New York

Zoya N. Demidenko

Oncotarget, Elmsford, New York

Claire Vivo

Ordway Research Institute, Albany, New York

Mari E. Swift

University of Illionis at Chicago, Chicago, Illinois

Brian M. Davis

Ordway Research Institute, Albany, New York

Mikhail V. Blagosklonny

Blagosklonny

Igor B. Roninson

Ordway Research Institute

Purchase article for $19

Subscribe to this journal for $129/year