REGULATION OF HEAT SHOCK FACTOR BY HSBP1

HSBP1 对热休克因子的调节

• 批准号: 6014611
• 负责人: SALLY Maureen MCFALL
• 金额: $ 3.17万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-18 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6014611
• 关键词: binding proteins; gene expression; gene mutation; protein protein interaction; protein structure function; stress proteins; tissue /cell culture; transcription factor; transfection; yeast two hybrid system

Heat shock proteins (hsps) are rapidly produced at high levels in response to stress. They function in the cell to aid in proper protein folding and translocation and to prevent inappropriate protein aggregation. The accumulation of misfolded proteins is central to diseases of protein folding, including sickle cell haemoglobin, cystic fibrosis and prion diseases, in addition to multifactorial diseases such as bacterial and viral infections, myocardial ischaemia, neurodegenerative diseases and cancer. Heat shock factor 1 (HSF1) is the major stress-responsive transcriptional activator of heat shock proteins. Heat shock binding protein 1 (HSBP1) interacts with HSF1 and negatively regulates its activity through an unknown mechanism. The interaction between HSF1 and HSBP1 negatively regulates HSF1 transcriptional activity. This association mediates a change in at least one step of the multiphase process of HSF1 activation and attenuation. The proposed research plan is to determine the mechanism of HSBP1 regulation of HSF1 activity. By the overexpression of HSBP1 and the expression of a dominant negative mutant of HSBP1, the affect of HSBP1 on individual characteristics of HSF1 activation/attenuation will be determined. In addition, the structure/function relationship of HSBP1 will be investigated by random mutagenesis studies. We also propose determining the temporal and spatial relationship of the HSBP1 regulation of HSF1 in order to propose a model for the regulation of protein homeostasis during the cellular stress response.

热休克蛋白（HSP）响应应力而在高水平上迅速产生。 它们在细胞中起作用，以帮助适当的蛋白质折叠和易位，并防止不适当的蛋白质聚集。 错误折叠蛋白的积累是蛋白质折叠疾病的核心，包括镰状细胞血红蛋白，囊性纤维化和prion病，除了多因素疾病，例如细菌和病毒感染，心肌局部疾病，神经性疾病和癌症。热休克因子1（HSF1）是热休克蛋白的主要应力转录激活剂。 热休克结合蛋白1（HSBP1）与HSF1相互作用，并通过未知机制对其活性进行负调节。 HSF1和HSBP1之间的相互作用对HSF1转录活性负调节。 该关联介导了HSF1激活和衰减的多相过程的至少一步的变化。 拟议的研究计划是确定HSBP1调节HSF1活性的机制。 通过HSBP1的过表达和汇丰银行的显性阴性突变体的表达，将确定汇丰银行对HSF1激活/衰减个体特征的影响。 此外，将通过随机诱变研究研究汇丰银行的结构/功能关系。 我们还建议确定HSBP1调节HSF1的时间和空间关系，以提出一个模型，以调节细胞应激反应过程中蛋白质稳态的调节。