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.

为了应对压力，热休克蛋白 (hsps) 会快速产生高水平。 它们在细胞中发挥作用，帮助蛋白质正确折叠和易位，并防止不适当的蛋白质聚集。 错误折叠蛋白质的积累是蛋白质折叠疾病的核心，包括镰状细胞血红蛋白、囊性纤维化和朊病毒疾病，以及细菌和病毒感染、心肌缺血、神经退行性疾病和癌症等多因素疾病。热休克因子 1 (HSF1) 是热休克蛋白的主要应激反应性转录激活因子。 热休克结合蛋白 1 (HSBP1) 与 HSF1 相互作用，并通过未知机制负向调节其活性。 HSF1 和 HSBP1 之间的相互作用负向调节 HSF1 转录活性。 这种关联介导 HSF1 激活和减弱多相过程中至少一个步骤的变化。 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HSBP1的显性失活突变体的表达，将确定HSBP1对HSF1激活/减弱的个体特征的影响。 此外，HSBP1的结构/功能关系将通过随机诱变研究进行研究。 我们还建议确定 HSBP1 对 HSF1 调节的时间和空间关系，以便提出细胞应激反应期间蛋白质稳态调节的模型。