Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events
- Caterina Nardella1,2,
- Zhenbang Chen1,2,
- Leonardo Salmena1,2,6,
- Arkaitz Carracedo1,2,6,
- Andrea Alimonti1,2,
- Ainara Egia1,2,
- Brett Carver2,3,
- William Gerald4,
- Carlos Cordon-Cardo2,5, and
- Pier Paolo Pandolfi1,2,7
- 1 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 2 Cancer Biology and Genetics Program, Sloan-Kettering Institute, New York, New York 10021, USA;
- 3 Department of Surgery, Division of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
- 4 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
- 5 Department of Pathology, Columbia University, New York, New York 10032, USA
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↵6 These authors contributed equally to this work.
Abstract
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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Footnotes
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↵7 Corresponding author.
↵7 E-MAIL ppandolf{at}bidmc.harvard.edu; FAX (617) 667-0610.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1699608.
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- Received March 3, 2008.
- Accepted June 10, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press
