Role of ubiquitylation in renal cancer

泛素化在肾癌中的作用

基本信息

批准号：
8516794
负责人：
Maria F Czyzyk-Krzeska
金额：
$ 7.85万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2007-09-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516794
关键词：
Accounting Adult Amino Acids Angiogenic Factor Binding Biochemical Blood Vessels C-terminal Cancer Etiology Cessation of life Chromatin Complex Conventional (Clear Cell) Renal Cell Carcinoma Data Development Diagnosis Disease Early Diagnosis Enzymes Event Exhibits Gene Expression Profile Genetic Markers Goals Human Hydroxylation Hypoxia In Vitro Individual Kidney Laboratories Lead Link Lysine Malignant Epithelial Cell Malignant Neoplasms Mediating Messenger RNA Mixed Function Oxygenases Modification Molecular Mutation Neoplasms Nude Mice Oncogenic Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Play Polyubiquitin Process Procollagen-Proline Dioxygenase Proline Property Proteins RNA Polymerase II RNA polymerase II largest subunit Regulation Renal Cell Carcinoma Renal carcinoma Research Research Personnel Risk Role Signal Pathway Staging Structure Surface Symptoms Syndrome Tissues Tumor Suppressor Proteins Ubiquitin VHL gene Von Hippel-Lindau Tumor Suppressor Protein Work angiogenesis base carcinogenesis design environmental change experience improved in vivo indium arsenide loss of function mortality mutant novel outcome forecast programs reconstitution response transcription factor tumor tumorigenesis ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Renal cancer accounts for 3% of adult malignancies in the US, and is the 6th leading cause of cancer mortality. In this application, we propose to examine the molecular basis of the oncogenic process leading to the most common form of kidney cancer, renal clear cell carcinoma (RCC). There is a well established link between RCC oncogenesis and the loss of function of the von Hippel-Lindau tumor suppressor protein (pVHL). It is known that this oncogenic effect can be mediated through disruption of HIFa ubiquitylation. However, in this application, we will expand on our previous work implicating a novel pVHL-dependent signaling pathway in the development of RCC: the hydroxylation of the large subunit of RNA Polymerase II (RNAPII), Rpb1, and its subsequent ubiquitylation by the pVHL tumor suppressor complex. Our working hypothesis is that P1465 hydroxylation and pVHL-dependent ubiquitylation of Rpb1 provide fine tuning of the RNAPII complex's transcriptional activity, which results in patterns of gene expression that facilitate appropriate responses to environmental changes (such as oxidative stress). We propose that loss of that fine-tuning results in dysfunctional activity of RNAPII leading to oncogenesis. The overall goal of this work is to understand the mechanism of pVHL-dependent Rpb1 hydroxylation and ubiquitylation, and to assess the role that disruption of this process plays in oncogenesis. To achieve this, we will 1) identify the lysines within ubiquitin and Rpb1 that participate in pVHL-dependent polyubiquitylation of Rpb1 in a P1465-dependent manner in response to oxidative stress; 2) identify the prolyl hydroxylases involved in hydroxylation of Rpb1; 3) determine the oncogenic properties of Rpb1 mutants that do not undergo pVHL-dependent hydroxylation and ubiquitylation; and 4) assess the status of Rpb1 hydroxylation and ubiquitylation in human RCC tumors as compared to normal kidney tissue. The prognosis for patients with RCC is much better if their cancer is diagnosed in early stages; however, early diagnosis is uncommon in RCC because patients often do not experience symptoms until advanced stages of the disease. Because this research explores a novel biochemical mechanism for disease development, it could improve the prognosis for RCC patients in two ways: 1) by contributing to the development of new drugs to treat RCC, and 2) by identifying new genetic markers that could be used to identify individuals at risk for developing RCC.

描述（由申请人提供）：肾癌占美国成人恶性肿瘤的3％，是癌症死亡率的第六个主要原因。在此应用中，我们建议检查导致肾癌最常见形式的致癌过程的分子基础，肾透明细胞癌（RCC）。 RCC肿瘤发生与von Hippel-Lindau抑制蛋白（PVHL）的功能丧失之间存在良好的联系。众所周知，这种致癌作用可以通过破坏HIFA泛素化来介导。但是，在此应用中，我们将扩展我们以前的工作，这意味着RCC开发中的一种新型PVHL依赖性信号通路：RNA聚合酶II（RNAPII）的大亚基（RNAPII），RPB1的羟基化及其随后通过PVHL抑制肿瘤抑制剂复合物的泛素化。我们的工作假设是，RPB1的P1465羟基化和PVHL依赖性泛素化提供了RNAPII复合物的转录活性的微调，这导致基因表达的模式，从而促进对环境变化的适当反应（例如氧化应激）。我们提出，微调的丧失会导致RNAPII的功能失调，从而导致肿瘤发生。这项工作的总体目标是了解PVHL依赖性RPB1羟基化和泛素化的机制，并评估破坏这一过程在肿瘤发生中起作用的作用。为了实现这一目标，我们将1）识别泛素和RPB1中的赖氨酸，这些赖氨酸依赖于氧化应激，以P1465依赖性方式参与RPB1的PVHL依赖性多泛素化； 2）确定参与RPB1羟基化的羟基羟基酶； 3）确定不经历PVHL依赖性羟基化和泛素化的RPB1突变体的致癌特性； 4）与正常肾脏组织相比，评估人RCC肿瘤中RPB1羟基化和泛素化的状态。如果在早期诊断出癌症的癌症，对RCC患者的预后要好得多。但是，在RCC中，早期诊断并不常见，因为在疾病的晚期阶段，患者通常不会出现症状。因为这项研究探讨了一种新型的疾病发展生化机制，所以它可以通过两种方式改善RCC患者的预后：1）通过促进新药物来治疗RCC的开发，以及2）通过识别可用于识别有发展RCC风险的个体的新遗传标记。