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PMID: 8972227 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability.

Molecular and cellular biology ·Vol. 17 ·No. 1 ·1997-01-00 ·Pages 460-8

Kubbutat MH, Vousden KH

Abstract

The p53 tumor suppressor protein is activated in cells in response to DNA damage and prevents the replication of cells sustaining genetic damage by inducing a cell cycle arrest or apoptosis. Activation of p53 is accompanied by stabilization of the protein, resulting in accumulation to high levels within the cell. p53 is normally degraded through the proteasome following ubiquitination, although the mechanisms which regulate this proteolysis in normal cells and how the p53 protein becomes stabilized following DNA damage are not well understood. We show here that p53 can also be a substrate for cleavage by the calcium-activated neutral protease, calpain, and that a preferential site for calpain cleavage exists within the N terminus of the p53 protein. Treatment of cells expressing wild-type p53 with an inhibitor of calpain resulted in the stabilization of the p53 protein. By contrast, in vitro or in vivo degradation mediated by human papillomavirus E6 protein was unaffected by the calpain inhibitor, indicating that the stabilization did not result from inhibition of the proteasome. These results suggest that calpain cleavage plays a role in regulating p53 stability.

MeSH Terms
Adenosine Triphosphate/analogs & derivatives,pharmacology Adenylyl Imidodiphosphate/pharmacology Amino Acid Sequence Breast Neoplasms Calpain/antagonists & inhibitors,metabolism Carcinoma Chelating Agents/pharmacology Cysteine Proteinase Inhibitors/pharmacology Edetic Acid/pharmacology Humans Molecular Sequence Data Mutation Oncogene Proteins, Viral/metabolism Papillomaviridae Repressor Proteins Tumor Cells, Cultured Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
Chelating Agents Cysteine Proteinase Inhibitors E6 protein, Human papillomavirus type 16 Oncogene Proteins, Viral Repressor Proteins Tumor Suppressor Protein p53 Adenylyl Imidodiphosphate adenosine 5'-O-(3-thiotriphosphate) Adenosine Triphosphate Edetic Acid Calpain
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Kubbutat M H
ABL Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Vousden K H
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.17.1.460
Published
1997-01-00
Pages
460-8
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231771
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.17.1.460 PMC Full Text View journal details
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