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.