Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma.
Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma.
复制标题
透明细胞肾细胞癌中PVHL和MTORC1途径之间的相互作用。
DOI：
10.1158/1541-7786.mcr-11-0302
复制
发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Brugarolas J
中科院分区：
文献类型：
--
作者：
Kucejova B;Peña-Llopis S;Yamasaki T;Sivanand S;Tran TA;Alexander S;Wolff NC;Lotan Y;Xie XJ;Kabbani W;Kapur P;Brugarolas J
哺乳动物雷帕霉素复合体靶标1(MTORC1)与细胞生长控制有关，受到广泛的调控。我们以前报道过，在低氧条件下，mTORC1受到发育调控蛋白和DNA损伤反应1(Redd1)的抑制。Redd1被HIF-1上调，强制表达Redd1足以抑制mTORC1的表达。Redd1诱导的mTORC1抑制依赖于结节性硬化症复合体(TSC)1和2(TSC2)蛋白形成的蛋白质复合体。在肾透明细胞癌(CcRCC)中，von Hippel-Lindau(VHL)基因经常失活，导致HIF-2和/或HIF-1的结构性激活，可能上调Redd1并抑制mTORC1。然而，mTORC1在肾细胞癌中经常被激活，mTORC1抑制剂对这种类型的肿瘤有效；这是一个悖论。在电子芯片分析中，以及定量实时聚合酶链式反应、Western印迹和免疫组织化学的方法中，Redd1在VHL缺陷型ccRCC中上调。在小鼠模型中，VHL的破坏足以诱导Redd1。利用ccRCC来源的细胞系，我们证明了肿瘤中Redd1的上调是VHL依赖的，并且HIF-1和HIF-2都以细胞类型依赖的方式被招募到Redd1的诱导中，并且对Redd1的诱导是必不可少的。有趣的是，虽然在一些肿瘤中mTORC1对Redd1有反应，但在其他肿瘤中已经进化了策略，例如破坏TSC1的突变，以破坏Redd1对mTORC1的抑制。以PTEN为参照，对77例ccRCC进行了TSC1、TSC2和Redd1突变的测序分析，提示TSC1基因，可能还有Redd1，在散发性ccRCC中是肿瘤抑制基因。了解ccRCC如何变得对Redd1诱导的mTORC1抑制无效将有助于ccRCC的发展，并可能有助于分子靶向治疗的患者选择。
Mammalian target of rapamycin complex 1 (mTORC1) is implicated in cell growth control and is extensively regulated. We previously reported that in response to hypoxia, mTORC1 is inhibited by the protein regulated in development and DNA damage response 1 (REDD1). REDD1 is upregulated by HIF-1, and forced REDD1 expression is sufficient to inhibit mTORC1. REDD1-induced mTORC1 inhibition is dependent on a protein complex formed by the tuberous sclerosis complex (TSC)1 and 2 (TSC2) proteins. In clear-cell renal cell carcinoma (ccRCC), the von Hippel-Lindau (VHL) gene is frequently inactivated leading to constitutive activation of HIF-2 and/or HIF-1, which may be expected to upregulate REDD1 and inhibit mTORC1. However, mTORC1 is frequently activated in ccRCC and mTORC1 inhibitors are effective against this tumor type; a paradox herein examined. REDD1 was upregulated in VHL-deficient ccRCC by in silico microarray analyses, as well as by quantitative real-time PCR, Western blot, and immunohistochemistry. Vhl disruption in a mouse model was sufficient to induce Redd1. Using ccRCC-derived cell lines, we show that REDD1 upregulation in tumors is VHL-dependent, and that both HIF-1 and HIF-2 are, in a cell-type dependent manner, recruited to, and essential for, REDD1 induction. Interestingly, whereas mTORC1 is responsive to REDD1 in some tumors, strategies have evolved in others, such as mutations disrupting TSC1, to subvert mTORC1 inhibition by REDD1. Sequencing analyses of 77 ccRCCs for mutations in TSC1, TSC2 and REDD1, using PTEN as a reference, implicate the TSC1 gene, and possibly REDD1, as tumor suppressors in sporadic ccRCC. Understanding how ccRCCs become refractory to REDD1-induced mTORC1 inhibition should shed light into the development of ccRCC and may aid in patient selection for molecular targeted therapies.