PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy.
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.
Mayo
Lindsey D
LD
Department of Microbiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Dixon
Jack E
JE
Durden
Donald L
DL
Tonks
Nickolas K
NK
Donner
David B
DB
D015153:Blotting, Western; D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D004396:Coloring Agents / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005047:Etoposide / Q000494:pharmacology; D017930:Genes, Reporter; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D018613:Microscopy, Confocal; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism* / Q000502:physiology*; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000502:physiology*
D004396:Coloring Agents; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C022616:thiazolyl blue