权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Inhibition of the Tubulin Folding Pathway as a Novel Therapy for Cancer

抑制微管蛋白折叠途径作为癌症的新疗法

基本信息

批准号：
7615339
负责人：
NICHOLAS COWAN
金额：
$ 9.48万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2007-07-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7615339
关键词：
Affect Affinity Antineoplastic Agents Binding Biological Assay Cancerous Cell Cycle Arrest Cell Death Cell division Cell physiology Cells Chemotherapy-Oncologic Procedure Classification Clinical Clinical Trials Collaborations Color Compatible Complex Condition Cultured Cells Development Disease Drug Delivery Systems EEF1A1 gene Environment Eukaryotic Cell GTPase-Activating Proteins Generations Genes Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Hereditary Disease Human Hydrolysis Inherited Kinetics Letters Libraries Malignant Neoplasms Measures Mediating Methods Microtubule Polymerization Microtubules Mitotic spindle Molecular Chaperones Monitor Morphologic artifacts Mutation Numbers Pathogenesis Pathway interactions Peptide Elongation Factor Tu Pharmaceutical Preparations Play Polymers Production Proliferating Proteins Reaction Ribosomes Role Screening procedure Series Small Interfering RNA Structure Temperature Testing Tubulin Validation base cancer cell cancer therapy chaperonin CCT cofactor concept cytosolic chaperonin experience high throughput screening human EEF1A1 protein human disease inorganic phosphate novel polymerization polypeptide research study scale up size tubulin-specific chaperone C

项目摘要

Microtubules are dynamic polymers that play an important role in many vital cellular functions. They are assembled from heterodimers consisting of one a- and one (3-tubulin polypeptide. The participation of microtubules in cell division as an essential component of the mitotic spindle has made these structures attractive targets for cancer chemotherapy: several drugs that interfere with normal microtubule dynamics are currently in clinical use and many other such compounds are currently undergoing clinical trials. Microtubules are thus well established as a validated and highly successful anti-cancer target. All of the currently known compounds that interfere with microtubule dynamics do so by binding to tubulin, but none are known that interfere with the pathway leading to the de novo assembly of the tubulin heterodimer. This pathway involves interaction of newly synthesized tubulin polypeptides with a series of chaperone proteins, beginning with the cytosolic chaperonin CCT. Quasi-native subunits released from CCT interact with several tubulin-specific chaperones (known as cofactors A-E) in a reaction that leads to release of newly generated heterodimers following GTP hydrolysis by cofactor-bound (3-tubulin. Cofactors C, D and E also function as a GTPase activating protein (GAP) for tubulin; this reaction is distinct from the GTP hydrolysis that accompanies microtubule polymerization in that it occurs at a much lower tubulin concentration. Because cofactors C, D and E are essential for tubulin heterodimer formation, they represent unique and novel potential targets for interfering with the generation of productively folded tubulin heterodimers. Experiments using systematic siRNA knockdown and our recent analysis of a human genetic disorder (HRD) involving cofactor E provide proof-of-concept and further functional validation for this approach. The experiments we propose are intended to lay the groundwork for a search for compounds that interfere with de novo tubulin heterodimer formation. We will 1) Develop the tubulin GAP assay for application to a high throughput format; 2) Devise methods for the optimization of cofactor production for use in high throughput assays; 3) Develop methods for the elucidation of the mechanism of inhibition in tubulin GAP assays in order to eliminate artifacts and prioritize compounds for further study; and 4) Perform pilot high throughput screens in order to establish appropriate conditions, optimize our assays, and define thresholds and hits.

微管是一种动态聚合物，在许多重要的细胞功能中起着重要作用。他们