PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy

Lindsey Mayo, Jack E. Dixon, Donald L. Durden, Nickolas K. Tonks, David B. Donner

Research output: Contribution to journalArticle

256 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5484-5489
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number7
DOIs
StatePublished - Feb 15 2002

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Tumor Suppressor Proteins
Chemotherapy
Tumors
Genes
Cells
Phosphatidylinositol 3-Kinase
Tumor Suppressor Protein p53
Drug Therapy
Etoposide
Null Lymphocytes
Gene expression
Neoplasms
Glioblastoma
Feedback
PTEN Phosphohydrolase
DNA
p53 Genes
Cell Cycle Checkpoints
Transcriptional Activation
DNA Damage

ASJC Scopus subject areas

  • Biochemistry

Cite this

PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. / Mayo, Lindsey; Dixon, Jack E.; Durden, Donald L.; Tonks, Nickolas K.; Donner, David B.

In: Journal of Biological Chemistry, Vol. 277, No. 7, 15.02.2002, p. 5484-5489.

Research output: Contribution to journalArticle

Mayo, Lindsey ; Dixon, Jack E. ; Durden, Donald L. ; Tonks, Nickolas K. ; Donner, David B. / PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 7. pp. 5484-5489.
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