Renal Division, Department of Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Sci Rep. 2021 Jul 21;11(1):14827. doi: 10.1038/s41598-021-94132-5.
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.
抑癌基因 von Hippel-Lindau（VHL）的失活是遗传性和散发性肾透明细胞癌（ccRCC）的关键事件。雷帕霉素（mTOR）信号通路的机械靶标是细胞生长和增殖的基本调节剂，mTOR 信号的过度激活是 VHL 依赖性 ccRCC 的常见发现。mTOR 信号的失调与 ccRCC 患者的肿瘤进展和不良预后相关。在这里，我们报告说，mTOR 的调节相关蛋白（RAPTOR）被 VHL 显著抑制。VHL 与 RAPTOR 相互作用，并通过泛素化增加 RAPTOR 的降解，从而抑制 mTORC1 信号。与 VHL 缺陷型 ccRCC 中 mTORC1 信号的过度激活一致，我们观察到秀丽隐杆线虫中 vhl-1 功能的丧失增加了 mTORC1 的活性，支持了一种进化保守的机制。我们的工作揭示了 ccRCC 中 mTORC1 信号失调的重要新机制，并将 VHL 直接与 RAPTOR/mTORC1 的控制联系起来。这可能代表了一种新的机制，即 VHL 的缺失影响器官完整性和肿瘤行为。
