Gene repression by HSF1 during hyperthermia and other stresses.

高温和其他应激期间 HSF1 的基因抑制。

基本信息

批准号：
7897641
负责人：
STUART Keith CALDERWOOD
金额：
$ 22.7万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897641
关键词：
Address Affect Agonist Biological Breast Carcinoma Cells Cellular Stress Chromatin Complex Development ERBB2 gene Estrogen Receptors Estrogen receptor positive Estrogens Fever Gene Expression Genes Genetic Transcription Grant Heat shock proteins Heat-Shock Proteins 70 Heregulin Histone Acetylation Human Lead Malignant Neoplasms Mammary Neoplasms Mediating Molecular Machines Neoplasm Metastasis NuRD complex Oncogenic Outcome Pathway interactions Pattern Phenotype Play Proteins Proto-Oncogenes Recruitment Activity Regulation Relative (related person)Reporter Repression Resistance Role Sampling Stress Tissues Treatment outcome biological adaptation to stress c-myc Genes cancer therapy cohort gene repression heat-shock factor 1 human HDAC1 protein malignant breast neoplasm migration neoplastic cell outcome forecast overexpression promoter protein complex protein protein interaction transcription factor tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The cohort of heat shock proteins (HSP) induced by cell stress becomes expressed at high levels in a wide range of tumors and is closely associated with a poor prognosis and resistance to cancer therapy. In addition, hsp are often induced by cancer therapy and may thus participate in resistance pathways, increased HSP transcription in tumor cells is due to the transcription factor heat shock factor 1 (HSF1) and plays an essential role in tumorigenesis. We have determined that HSF1 is a potent represser of non-hsp genes in tumor cells in addition to its role as an activator of hsp gene transcription. We have recently shown that the mechanism of gene repression includes recruitment by HSF1 of the powerful NuRD co-repressor complex which contains metastasis associated protein 1 (MTA1) as a major organizing component. Elevated expression of HSF1 correlates with increased MTA1 levels in advanced breast cancer. In this proposal, we will examine the role of the HSF1 / MTA1 / NuRD complex in the mechanisms of gene repression by HSF1 and the role of HSF1 repression the development of a metastatic phenotype. We will investigate the hypothesis that this complex can be recruited by the HER2 proto-oncogene agonist heregulin and can repress estrogen-inducible transcription and thus lead to pro-metastatic changes by switching the pattern of gene expression.

描述（由申请人提供）：由细胞应激诱导的热激蛋白（HSP）的队列在广泛的肿瘤中以高水平表达，并且与预后不良和对癌症治疗的耐药性密切相关。此外，HSP通常是由癌症治疗诱导的，因此可能参与抗性途径，肿瘤细胞中的HSP转录增加是由于转录因子热休克因子1（HSF1）引起的，并且在肿瘤发生中起着至关重要的作用。我们已经确定HSF1是肿瘤细胞中非HSP基因的有效抑制剂，除了其作为HSP基因转录激活剂的作用。我们最近表明，基因抑制的机制包括HSF1强大的NURD共抑制剂复合物的募集，该复合物包含转移相关的蛋白1（MTA1）作为主要的组织成分。 HSF1的表达升高与晚期乳腺癌中MTA1水平升高相关。在此提案中，我们将研究HSF1 / MTA1 / NURD复合物在HSF1基因抑制机理中的作用，而HSF1抑制的作用是转移性表型的发展。我们将研究以下假设：这种复合物可以由HER2原始癌基因激动剂在这里募集，并可以抑制雌激素可诱导的转录，从而通过切换基因表达的模式来导致促异常变化。