Endogenous tumor suppression mediated by PTEN involves survivin gene silencing.
Endogenous tumor suppression provides a barrier against oncogenesis, but the molecular requirements of this process are not well understood. Here, we show that the dual specificity phosphatase PTEN, a gene almost universally altered in human tumors, silences the expression of survivin, an essential regulator of cell division and apoptosis in cancer. This pathway is independent of p53, involves active repression of survivin gene transcription, and is mediated by direct occupancy of the survivin promoter by FOXO1 and FOXO3a factors. Conditional deletion of PTEN in the mouse prostate causes deregulated induction of survivin before full-blown transformation in vivo, whereas expression of survivin and PTEN is inversely correlated in cancer patients. Therefore, silencing the survivin gene is an essential requirement of endogenous PTEN tumor suppression.
Guha
Minakshi
M
Department of Cancer Biology, Prostate Cancer Discovery and Development Program, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Plescia
Janet
J
Leav
Irwin
I
Li
Jing
J
Languino
Lucia R
LR
Altieri
Dario C
DC
D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D051858:Forkhead Transcription Factors / Q000502:physiology; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D000077022:Survivin; D014158:Transcription, Genetic
C107489:BIRC5 protein, human; D017931:DNA Primers; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human