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。

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.