Growth Control and Anti-Cancer Drug Mechanisms

生长控制和抗癌药物机制

基本信息

批准号：
8444399
负责人：
STEVEN ZHENG
金额：
$ 7.47万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444399
关键词：
Aging Anabolism Antineoplastic Agents Area Binding Binding Sites Biogenesis Biological Biology CCI-779 Cancer Biology Cell Nucleus Cell physiology Cells Chromatin Clinic Clinical Trials Complex Cytoplasm Diabetes Mellitus Disease Drug Targeting Endometrial Carcinoma Event Experimental Models Gene Expression Genes Genetic Transcription Genomics Goals Growth Heart Hypertrophy Histone Deacetylase Human Link Malignant Neoplasms Mediating Metabolic Metabolic Diseases Metabolism Molecular Muscular Dystrophies Mutate Mutation Nuclear Nutrient Parkinson Disease Pathogenesis Pathologic Processes Pathway interactions Pharmacotherapy Phosphotransferases Play Polycystic Kidney Diseases Polymerase Process Protein Biosynthesis Protein Inhibition Protein Kinase Protein-Serine-Threonine Kinases Proteins RNA Polymerase III Recombinant Proteins Renal Cell Carcinoma Renal carcinoma Research Resistance Ribosomal RNA Ribosomes Role Signal Transduction Sirolimus Testing Therapeutic Transcriptional Regulation Transfer RNA Translational Regulation Translations cancer addiction cancer therapy cell growth drug mechanism human disease improved inhibitor/antagonist insight mRNA Decay mRNA Export novel outcome forecast promoter protein metabolism response tumor tumorigenesis

项目摘要

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.

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）的特定靶标。它是细胞生长和代谢的中心控制器。 PI3K-TOR途径在超过50％的人类肿瘤中突变，导致TOR过度激活和不受控制的癌症生长。由于癌症成瘾的途径，TOR被公认为是抗癌药物治疗的主要靶标。 TOR的翻译起始调节是众所周知的生长控制机制。由于翻译主要是胞质事件，因此Tor在历史上被视为经典的细胞质激酶。但是，我们已经观察到Tor位于核中，并与核糖体基因的启动子结合以刺激其表达。我们进一步表明，阻止此过程对于雷帕霉素抑制细胞生长很重要。新兴的证据表明，对基因表达的控制，特别是涉及核糖体生物发生的基因以及与蛋白质合成和代谢生物合成有关的其他基因，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与TOR相关的疾病有关。与翻译控制相反，TOR信号传导对转录调控和其他核功能的理解非常有限。在此应用中，我们将检验以下假设：TOR在雷帕霉素敏感的转录和核内其他基因组功能中具有广泛的作用。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。这项提案的完成应为对TOR调节的核过程提供宝贵的新见解，这些见解知之甚少，但与癌症和代谢疾病的生物学和治疗高度相关。