Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified.
The capacity of DNA damaging agents to induce apoptosis is regulated by target gene induction by p53. We found that p53 targeted MDM2 in cells in which DNA repair was occurring, but persistent DNA damage induced by chemotherapy led p53 to selectively target PTEN. High dose chemotherapy induced the phosphorylation of p53 on serine 46, whereas low dose chemotherapy did not. A nonphosphorylatable serine 46 to alanine p53 mutant (S46A) targeted the MDM2 promoter in preference to that for PTEN. A serine 46 to aspartate mutant (S46D, a phosphorylation mimic) targeted PTEN in preference to MDM2. These observations show that phosphorylation of serine 46 in p53 is sufficient for it to induce the PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor protein in preference to MDM2. S46A induced significantly less cell death than the S46D in cells. The phosphorylation-induced change of p53 promoter targeting suppresses the induction of MDM2 and the formation of the autoregulatory feedback loop. Induction of PTEN by p53 followed by expression of PTEN inhibits AKT-induced translocation of MDM2 into the nucleus and sustains p53 function. The protection of p53 from MDM2 by PTEN and the damage-induced activation of PTEN by phosphorylated p53 leads to the formation of an apoptotic amplification cycle in which p53 and PTEN coordinately increase cellular apoptosis.
Mayo
Lindsey D
LD
Department of Radiation Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA. lindsey.mayo@cwru.edu
Seo
Young Rok
YR
Jackson
Mark W
MW
Smith
Martin L
ML
Rivera Guzman
Javier
J
Korgaonkar
Chandrashekhar K
CK
Donner
David B
DB
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D020552:Comet Assay; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry*; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012694:Serine; D012313:RNA; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human