Journal
GENES & DEVELOPMENT
Volume 22, Issue 16, Pages 2172-2177Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1699608
Keywords
Rheb; Pten haploinsufficiency; prostate tumorigenesis; negative feedback loop; senescence
Categories
Funding
- American-Italian Cancer Foundation
- HFSP
- EMBO
- MMHCC
- NCI
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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.
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