Regulation of PTEN transcription by p53.
PTEN tumor suppressor is frequently mutated in human cancers and is a negative regulator of PI3'K/PKB/Akt-dependent cellular survival. Investigation of the human genomic PTEN locus revealed a p53 binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wild-type p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts. Our results reveal a unique role for p53 in regulation of cellular survival and an interesting connection in tumor suppressor signaling.
Stambolic
V
V
Amgen Research Institute and, Ontario Cancer Institute, 620 University Avenue, Ontario, Toronto, Canada.
MacPherson
D
D
Sas
D
D
Lin
Y
Y
Snow
B
B
Jang
Y
Y
Benchimol
S
S
Mak
T W
TW
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000502:physiology; D005720:Gamma Rays; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013696:Temperature; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human