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PMID: 18708577 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events.

Genes & development ·Vol. 22 ·No. 16 ·2008-08-15 ·Pages 2172-7

Nardella C, Chen Z, Salmena L, Carracedo A, Alimonti A, Egia A, Carver B, Gerald W, Cordon-Cardo C, Pandolfi PP

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.

MeSH Terms
Animals Blotting, Western Cell Line, Tumor Cell Transformation, Neoplastic/pathology Chromosome Aberrations Humans Male Mechanistic Target of Rapamycin Complex 1 Mice Mice, Transgenic Monomeric GTP-Binding Proteins/physiology Multiprotein Complexes Neuropeptides/physiology PTEN Phosphohydrolase/physiology Prostatic Intraepithelial Neoplasia/etiology,metabolism,pathology Prostatic Neoplasms/etiology,metabolism,pathology Proteins Proto-Oncogene Mas RNA, Messenger/genetics,metabolism Ras Homolog Enriched in Brain Protein Reverse Transcriptase Polymerase Chain Reaction Signal Transduction TOR Serine-Threonine Kinases Transcription Factors/physiology
Chemicals
MAS1 protein, human Multiprotein Complexes Neuropeptides Proteins Proto-Oncogene Mas RHEB protein, human RNA, Messenger Ras Homolog Enriched in Brain Protein Transcription Factors Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases PTEN Phosphohydrolase Pten protein, mouse Monomeric GTP-Binding Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Nardella Caterina
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
Salmena Leonardo
Carracedo Arkaitz
Alimonti Andrea
Egia Ainara
Carver Brett
Gerald William
Cordon-Cardo Carlos
Pandolfi Pier Paolo
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1699608
Published
2008-08-15
Pages
2172-7
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2518820
Subset
IM
Grants
NIMHD NIH HHS · R01 MD004038 · United States
External Links
PubMed source DOI: 10.1101/gad.1699608 PMC Full Text View journal details
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