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.
Bibliographical noteFunding Information:
We thank Greg Arnold for help with sequence analysis, Angie Nelson for oligonucleotide synthesis, Ming-Sound Tsao for HBEC cells, Ayeda Ayed and Cheryl Arrowsmith for bacteria expressing recombinant p53, Joan Mangion for protein purification, and Malte Peters, Scott Pownall, Wen-Chen Yeh, and Mary Saunders for critical reading of the manuscript. V.S. is a recipient of a post-doctoral fellowship from the Cancer Research Institute, New York.