Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mol Cancer Res. 2011 Sep;9(9):1255-65. doi: 10.1158/1541-7786.MCR-11-0302. Epub 2011 Jul 28.
mTOR 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 hypoxia-inducible factor (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.
mTOR 复合物 1（mTORC1）参与细胞生长控制，并且受到广泛调节。我们之前报道过，在缺氧的情况下，mTORC1 受到发育和 DNA 损伤反应调节蛋白 1（REDD1）的抑制。REDD1 受缺氧诱导因子（HIF）-1 上调，强制表达 REDD1 足以抑制 mTORC1。REDD1 诱导的 mTORC1 抑制依赖于由结节性硬化复合物（TSC）1 和 2（TSC2）蛋白形成的蛋白质复合物。在透明细胞肾细胞癌（ccRCC）中，von Hippel-Lindau（VHL）基因经常失活，导致 HIF-2 和/或 HIF-1 的组成性激活，这可能导致 REDD1 的上调和 mTORC1 的抑制。然而，mTORC1 在 ccRCC 中经常被激活，并且 mTORC1 抑制剂对这种肿瘤类型有效；这里检查的悖论。通过计算机芯片微阵列分析以及实时定量 PCR、Western blot 和免疫组织化学，发现 VHL 缺陷型 ccRCC 中 REDD1 上调。在小鼠模型中破坏 Vhl 足以诱导 Redd1。使用 ccRCC 衍生的细胞系，我们表明肿瘤中 REDD1 的上调依赖于 VHL，并且 HIF-1 和 HIF-2 以细胞类型依赖性方式募集到并对 REDD1 的诱导至关重要。有趣的是，虽然在某些肿瘤中 mTORC1 对 REDD1 有反应，但在其他肿瘤中，例如破坏 TSC1 的突变，已经进化出了策略来破坏 REDD1 对 mTORC1 的抑制。使用 PTEN 作为参考，对 77 例 ccRCC 进行 TSC1、TSC2 和 REDD1 突变的测序分析，表明 TSC1 基因，可能还有 REDD1，是散发性 ccRCC 的肿瘤抑制因子。了解 ccRCC 如何对 REDD1 诱导的 mTORC1 抑制产生抗性，应该可以深入了解 ccRCC 的发生发展，并可能有助于为分子靶向治疗选择患者。
