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

被引：97

作者：

Nardella, Caterina ^{[1
,2
,3
]}

Chen, Zhenbang ^{[1
,2
,3
]}

Salmena, Leonardo ^{[1
,2
,3
]}

Carracedo, Arkaitz ^{[1
,2
,3
]}

Alimonti, Andrea ^{[1
,2
,3
]}

Egia, Ainara ^{[1
,2
,3
]}

Carver, Brett ^{[3
,4
]}

Gerald, William ^{[5
]}

Cordon-Cardo, Carlos ^{[3
,6
]}

Pandolfi, Pier Paolo ^{[1
,2
,3
]}

机构：

[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ct,Dept Med, Canc Genet Program,Beth Israel Deaconess Canc Ctr, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[3] Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10021 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Surg, Div Urol, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[6] Columbia Univ, Dept Pathol, New York, NY 10032 USA

来源：

GENES & DEVELOPMENT | 2008年 / 22卷 / 16期

关键词：

Rheb; Pten haploinsufficiency; prostate tumorigenesis; negative feedback loop; senescence;

D O I：

10.1101/gad.1699608

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：2172 / 2177

页数：6

共 31 条

[1] Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38 [J].