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：
9004605
负责人：
STEVEN ZHENG
金额：
$ 29.3万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
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 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9004605
关键词：
Aging Anabolism Antineoplastic Agents Area Binding Binding Sites Biogenesis Biological Biology Biosynthetic Proteins CCI-779 Cancer Biology Cell Nucleus Cell physiology Cells Cellular Metabolic Process 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 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 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 genomic profiles human disease improved inhibitor/antagonist insight mRNA Decay mRNA Export novel outcome forecast promoter protein metabolism response targeted treatment 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（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）的特定靶点。它是细胞生长和新陈代谢的中央控制器。超过 50% 的人类肿瘤中 PI3K-TOR 通路发生突变，导致 TOR 过度激活和不受控制的癌症生长。由于癌症成瘾途径，TOR被认为是抗癌药物治疗的主要靶点。 TOR 对翻译起始的调节是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，我们观察到TOR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。我们进一步表明，阻断这一过程对于雷帕霉素抑制细胞生长很重要。新的证据表明，基因表达的控制，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，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，我们将测试 TOR 在雷帕霉素敏感转录和细胞核内其他基因组功能中发挥广泛作用的假设。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。这项提案的完成将为 TOR 调节的核过程提供宝贵的新见解，该过程目前人们知之甚少，但与癌症和代谢疾病的生物学和治疗高度相关。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting the mTOR kinase domain: the second generation of mTOR inhibitors.

靶向 mTOR 激酶结构域：第二代 mTOR 抑制剂。

DOI：
10.1016/j.drudis.2011.02.008
发表时间：
2011-04
期刊：
Drug discovery today
影响因子：
7.4
作者：
Zhang, Yan-Jie;Duan, Yanwen;Zheng, X. F. Steven
通讯作者：
Zheng, X. F. Steven

Mechanisms of regulation of RNA polymerase III-dependent transcription by TORC1.

TORC1 调节 RNA 聚合酶 III 依赖性转录的机制。

DOI：
发表时间：
2009-08-05
期刊：
影响因子：
0
作者：
Wei, Yuehua;Tsang, Chi Kwan;Zheng, X F Steven
通讯作者：
Zheng, X F Steven

mTOR-independent 4E-BP1 phosphorylation is associated with cancer resistance to mTOR kinase inhibitors.

不依赖于 mTOR 的 4E-BP1 磷酸化与癌症对 mTOR 激酶抑制剂的耐药性相关。

DOI：
发表时间：
2012-02-01
期刊：
影响因子：
0
作者：
Zhang, Yanjie;Zheng, X F Steven
通讯作者：
Zheng, X F Steven

MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription.

MAF1 通过激活 PTEN 转录来抑制 AKT-mTOR 信号传导和肝癌。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Li, Yue;Tsang, Chi Kwan;Wang, Suihai;Li, Xiao;Yang, Yang;Fu, Liwu;Huang, Wenlin;Li, Ming;Wang, Hui;Zheng, X F Steven
通讯作者：
Zheng, X F Steven

Maf1 regulation: a model of signal transduction inside the nucleus.

Maf1 调节：细胞核内信号转导的模型。