PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy

Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K., Donner, D. B. (February 2002) PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. Journal of Biological Chemistry, 277 (7). pp. 5484-5489. ISSN 0021-9258

URL: http://www.ncbi.nlm.nih.gov/pubmed/11729185
DOI: 10.1074/jbc.M108302200

Abstract

The PTEN tumor suppressor protein inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling that promotes translocation of Mdm2 into the nucleus. When restricted to the cytoplasm, Mdm2 is degraded. The ability of PTEN to inhibit the nuclear entry of Mdm2 increases the cellular content and transactivation of the p53 tumor suppressor protein. Retroviral transduction of PTEN into U87MG (PTEN null) glioblastoma cells increases p53 activity and expression of p53 target genes and induces cell cycle arrest. U87MG/PTEN glioblastoma cells are more sensitive than U87MG/PTEN null cells to death induced by etoposide, a chemotherapeutic agent that induces DNA damage. Previously, tumor suppressor proteins have been supposed to act individually to suppress cancers. Our results establish a direct connection between the activities of two major tumor suppressors and show that they act together to respond to stresses and malignancies. PTEN protects p53 from survival signals, permitting p53 to function as a guardian of the genome. By virtue of its capacity to protect p53, PTEN can sensitize tumor cells to chemotherapy that relies on p53 activity. p53 induces PTEN gene expression, and here it is shown that PTEN protects p53, indicating that a positive feedback loop may amplify the cellular response to stress, damage, and cancer.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > MDM2
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
diseases & disorders > cancer > drugs and therapies > chemotherapy
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Tonks lab
Depositing User: Matt Covey
Date: February 2002
Date Deposited: 16 Dec 2013 17:41
Last Modified: 16 Dec 2013 17:41
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28745

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