异常的Rheb介导的mTORC1激活和Pten单倍体不足是协同致癌事件。
Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events.
作者信息
Nardella Caterina, Chen Zhenbang, Salmena Leonardo, Carracedo Arkaitz, Alimonti Andrea, Egia Ainara, Carver Brett, Gerald William, Cordon-Cardo Carlos, Pandolfi Pier Paolo
机构信息
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.
出版信息
Genes Dev. 2008 Aug 15;22(16):2172-7. doi: 10.1101/gad.1699608.
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.
雷帕霉素的哺乳动物靶点（mTOR）是一个关键的信号交叉点，癌症中常见的信号通路在此汇聚。我们在此报告，mTOR复合物1（mTORC1）的上游激活因子Rheb GTP酶在人类前列腺癌中发生扩增。我们证明，Rheb过表达促进小鼠前列腺增生和低级别肿瘤表型，同时引发伴随的衰老反应和限制Akt激活的负反馈回路。重要的是，我们表明Pten单倍体不足与Rheb过表达协同作用，显著促进前列腺肿瘤发生。我们得出结论，在适当的遗传环境和信号背景下，Rheb作为原癌基因发挥作用。
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