Mutated p21(WAF1/CIP1/SDI1) lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells

Y Lu; N Yamagishi; T Yagi; H Takebe

doi:10.1038/sj.onc.1201585

Mutated p21(WAF1/CIP1/SDI1) lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells

Oncogene. 1998 Feb 12;16(6):705-12. doi: 10.1038/sj.onc.1201585.

Authors

Y Lu¹, N Yamagishi, T Yagi, H Takebe

Affiliation

¹ Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Japan.

PMID: 9488034
DOI: 10.1038/sj.onc.1201585

Abstract

Human colorectal tumor cell lines were established which express wildtype p21 or p21 with a mutation at codon 46 (Cys) or 140 (Gly) on IPTG treatment (LacSwitch). The IPTG-induced wildtype p21 bound to CDK2 and PCNA and inhibited CDK activity in the cells and reduced cell growth rate; whereas, both IPTG-induced mutated p21 proteins neither bound to CDK2 nor affected the CDK activity but did bind to PCNA, and they did not affect the cell growth rate. Wildtype p21 suppressed apoptosis and enhanced survival of X-ray-irradiated or adriamycin-treated cells; but, mutated p21 neither suppressed apoptosis nor affected cell survival. When cells were treated with mimosine, a p53-independent p21-inducer, or butyrolactone I, a specific inhibitor of CDK, cellular endogenous p21 was induced and X-ray or adriamycin-induced apoptosis was blocked. These results suggest that CDK-binding or CDK-inhibitory activity of p21 is required to prevent apoptosis, i.e., CDK is required for apoptosis in human tumor cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

4-Butyrolactone / analogs & derivatives
4-Butyrolactone / pharmacology
Apoptosis* / radiation effects
CDC2-CDC28 Kinases*
Cell Survival
Colorectal Neoplasms
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases / metabolism*
Cyclins / genetics*
Cyclins / metabolism*
Doxorubicin / pharmacology
Enzyme Inhibitors / metabolism*
Humans
Isopropyl Thiogalactoside / pharmacology
Mimosine / pharmacology
Mutation*
Proliferating Cell Nuclear Antigen / metabolism
Protein Kinase Inhibitors
Protein Serine-Threonine Kinases / metabolism*
Tumor Cells, Cultured
X-Rays

Substances

CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
Enzyme Inhibitors
Proliferating Cell Nuclear Antigen
Protein Kinase Inhibitors
Isopropyl Thiogalactoside
Mimosine
Doxorubicin
butyrolactone I
Protein Serine-Threonine Kinases
CDC2-CDC28 Kinases
CDK2 protein, human
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases
4-Butyrolactone