Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events.
The mammalian target of rapamycin (mTOR) represents a critical signaling crossroad where pathways commonly disrupted in cancer converge. We report here that Rheb GTPase, the upstream activator of the mTOR complex 1 (mTORC1) is amplified in human prostate cancers. We demonstrate that Rheb overexpression promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate while eliciting a concomitant senescence response and a negative feedback loop limiting Akt activation. Importantly, we show that Pten haploinsufficiency cooperates with Rheb overexpression to markedly promote prostate tumorigenesis. We conclude that Rheb acts as a proto-oncogene in the appropriate genetic milieu and signaling context.
Nardella
Caterina
C
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Chen
Zhenbang
Z
Salmena
Leonardo
L
Carracedo
Arkaitz
A
Alimonti
Andrea
A
Egia
Ainara
A
Carver
Brett
B
Gerald
William
W
Cordon-Cardo
Carlos
C
Pandolfi
Pier Paolo
PP
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002869:Chromosome Aberrations; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology*; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019048:Prostatic Intraepithelial Neoplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000502:physiology*
C000715470:MAS1 protein, human; D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; D000090063:Proto-Oncogene Mas; C490211:RHEB protein, human; D012333:RNA, Messenger; D000076205:Ras Homolog Enriched in Brain Protein; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020559:Monomeric GTP-Binding Proteins