KCTD蛋白对TORC1信号通路的调控机制及对肿瘤生成的影响

Identifying new cancer driver gene and delineating its role in regulating cell growth is crucial to understand the pathogenesis of cancer and to develop new cancer treatment. We once developed a cancer progression model using yeast as a model organism and identified a yeast protein Whi2 as a tumor suppressor-like factor. KCTD family proteins are the human homologs of yeast Whi2, and have been reported to be frequently deleted or mutated in certain human cancers, indicating they are potentially novel tumor suppressors. We have found that yeast Whi2 is a negative regulator of TORC1 in response to amino acid signal. Preliminary data suggested that certain human KCTD protein shows similar inhibitory effect on mammalian TORC1 like Whi2, indicating KCTD proteins might function as tumor suppressors through regulating amino acid-sensing TORC1 signaling pathway. Amino acid-sensing TORC1 signaling pathway is highly conserved in eukaryotes. Its deregulation uncouples the nutrient signal and cell growth, leading to uncontrolled cell growth even in the nutrient-deprived environment, and has been considered to be the important cause for tumorigenesis. We will focus our studies on how human KCTD proteins regulate amino acid-sensing TORC1 signaling pathway in mammalian system, to further understand the mechanism of tumorigenesis, and identify new target for cancer treatment.

寻找新的癌症驱动基因并确定其对细胞生长的调控机制对了解癌症的发病机理及发展新的治疗手段有着重大意义。申请人以酵母为模式生物构建了一个癌症演进模型，发现了一个在功能上类似肿瘤抑制因子的酵母Whi2蛋白。其人类同源蛋白KCTD在某些肿瘤中经常性缺失或突变，是潜在的新肿瘤抑制因子。实验显示，酵母Whi2蛋白是氨基酸信号下TORC1复合物的负调控因子，而人类KCTD蛋白也有着和Whi2蛋白类似的对TORC1活性的抑制作用，预示KCTD可能通过调节氨基酸介导的TORC1信号通路影响细胞生长。氨基酸介导的TORC1信号通路在所有真核细胞中高度保守，其失调将导致细胞在营养匮乏的环境下仍持续生长，是癌症生成的重要起因。我们将重点研究人类KCTD蛋白对氨基酸介导的TORC1信号通路的调控机制，以便更好地理解肿瘤生成的分子机理，为癌症治疗提供新的靶点。

本研究以酵母为模式生物构建的癌症演进模型为依据，首次探讨人类KCTD蛋白在调节细胞生长的TORC1信号通路中的作用。通过构建KCTD过表达及基因沉默细胞模型，确认了某些KCTD蛋白如KCTD9、KCTD11和KCNRG在氨基酸信号下对TORC1活性有较强的抑制作用。因此当这些KCTD蛋白发生突变时，会导致TORC1活性升高，细胞生长过度，导致肿瘤生成。KCTD家族蛋白N端含有高度保守的四聚体结构域BTB，是其行使正常生物功能所必须的。基因上位性分析显示，KCDT/Whi2对TORC1活性的抑制作用独立于保守的氨基酸介导的GATOR1/SEACIT-RAG/Gtr通路，揭示KCTD/Whi2是新的氨基酸信号下RAG/Gtr蛋白复合物非依赖性的TORC1抑制因子，证实在细胞中可能存在多种营养信号感知机制。KCTD11及KCTD9可以和自噬相关蛋白p62、ATG5结合，暗示KCTD11和KCTD9可能通过调节TORC1活性调控其下游的自噬通路。进一步实验显示，KCTD发生突变会抑制氨基酸缺失条件下的自噬水平，而这可能是导致含有KCTD7突变的癫痫病人的致病原因。本研究首次阐明人类KCTD蛋白对调节细胞生长的TORC1活性有抑制作用，可正向调控自噬通路，具有肿瘤抑制因子的特性，并在神经系统中发挥重要作用。