VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma

被引:31
作者
Ganner, Athina [1 ]
Gehrke, Christina [1 ]
Klein, Marinella [1 ]
Thegtmeier, Lena [1 ]
Matulenski, Tanja [1 ]
Wingendorf, Laura [1 ]
Wang, Lu [1 ]
Pilz, Felicitas [1 ]
Greidl, Lars [1 ]
Meid, Lisa [1 ]
Kotsis, Fruzsina [1 ]
Walz, Gerd [1 ]
Frew, Ian J. [2 ]
Neumann-Haefelin, Elke [1 ]
机构
[1] Univ Freiburg, Fac Med, Med Ctr, Dept Med,Renal Div, Freiburg, Germany
[2] Univ Freiburg, Fac Med, Med Ctr, Dept Internal Med 1, Freiburg, Germany
关键词
CAENORHABDITIS-ELEGANS; ONCOGENIC DRIVER; KINASE-ACTIVITY; PATHWAY; DEGRADATION; METABOLISM; BINDING; PROTEIN; CANCER; PVHL;
D O I
10.1038/s41598-021-94132-5
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Inactivation of the tumor suppressor von Hippel-Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.
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页数:15
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