Growth Control and Anti-Cancer Drug Mechanisms

描述（由申请人提供）：TOR是一种高度保守的蛋白丝氨酸/苏氨酸激酶，是抗癌药物雷帕霉素和雷帕霉素类似物（rapalogs）的特异性靶点。它是细胞生长和代谢的中心控制者。PI3K-TOR通路在超过50%的人类肿瘤中发生突变，导致TOR超激活和不受控制的癌症生长。由于具有癌症成瘾的通路，TOR被认为是抗癌药物治疗的主要靶点。TOR调控翻译起始是一种众所周知的生长控制机制。由于翻译主要是细胞质事件，TOR历来被视为经典的细胞质激酶。然而，我们已经观察到TOR定位于细胞核中，并与核糖体基因的启动子结合以刺激其表达。我们进一步证明阻断这一过程对雷帕霉素抑制细胞生长很重要。越来越多的证据表明，控制基因表达，特别是参与核糖体生物发生的基因和其他参与蛋白质合成和代谢生物合成的基因，是TOR促进蛋白质合成和代谢的重要机制。这些过程的失调与肿瘤发生和其他tor相关疾病有关。与翻译控制相比，对TOR信号的转录调控和其他核功能的了解非常有限。在这个应用中，我们将检验TOR在细胞核内雷帕霉素敏感转录和其他基因组功能中具有广泛作用的假设。我们将进一步研究雷帕霉素通过Maf1和Rpd3抑制核糖体和其他蛋白质生物合成基因的分子机制。这一建议的完成将为tor调控的核过程提供宝贵的新见解，这一过程鲜为人知，但与癌症和代谢性疾病的生物学和治疗高度相关。

DESCRIPTION (provided by applicant): TOR is a highly conserved protein serine/threonine kinase and the specific target of the anticancer drug rapamycin and rapamycin analogs (rapalogs). It is a central controller of cell growth and metabolism. PI3K-TOR pathway is mutated in over 50% of human tumors, resulting in TOR hyper-activation and uncontrolled cancer growth. Because of the cancer addiction the pathway, TOR is recognized as a major target for anti-cancer drug therapy. TOR regulation of translational initiation is a well known mechanism of growth control. Because translation is predominantly a cytoplasmic event, TOR has been historically viewed as a classical cytoplasmic kinase. However, we have observed that TOR is localized in the nucleus and binds to the promoters of ribosomal genes to stimulate their expression. We further showed that blocking this process is important for rapamycin to inhibit cell growth. Emerging evidence indicates that control of gene expression, particularly genes involved in ribosome biogenesis and other genes involved in protein synthesis and metabolic biosynthesis, is an important mechanism for TOR to promote protein synthesis and metabolism. Dysregulation of these processes has been linked to tumorigenesis and other TOR-related diseases. In contrast to translational control, the understanding of transcriptional regulation and other nuclear functions by TOR signaling is very limited. In this application, we will test the hypothesis that TOR has a broad role in rapamycin- sensitive transcription and other genomic functions inside the nucleus. We will further investigate the molecular mechanisms by which rapamycin represses ribosomal and other protein biosynthetic genes through Maf1 and Rpd3. Accomplishment of this proposal should provide invaluable new insights into TOR-regulated nuclear process that is poorly understood but highly relevant to the biology and therapy of cancer and metabolic diseases.