Regulation and Function of Mammalian HSF4 in vivo

哺乳动物 HSF4 体内的调控和功能

• 批准号: 7665417
• 负责人: NAHID F MIVECHI
• 金额: $ 26.56万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665417
• 关键词: Ablation; Acceleration; Address; Affect; Anchorage-Independent Growth; Animal Model; Carcinogens; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell Survival; Cell physiology; Cells; Chemicals; Crying; Crystallins; Data; Defect; Development; Diethylnitrosamine; Disease; Down-Regulation; Epithelial Cells; Eukaryotic Cell; Event; Exhibits; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Grant; Growth; Heat shock proteins; Hepatic; Hepatocarcinogenesis; Hereditary Disease; Human; Inflammatory; Inflammatory Response; Intrinsic drive; Investigation; Laboratories; Long-Term Effects; Loss of Heterozygosity; Lymphoma; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Chaperones; Molecular Genetics; Mus; Muscle Fibers; Mutation; Myoblasts; Neoplastic Cell Transformation; Oncogenic; Organism; Pathogenesis; Pathway interactions; Pattern; Physiological; Play; Population; Primary Neoplasm; Primary carcinoma of the liver cells; Process; Production; Property; Protein Isoforms; Public Health; Publishing; RNA Splicing; Regulation; Resistance; Rhabdomyosarcoma; Role; Stem cells; Stress; TP53 gene; Testing; Therapeutic; Tumor Suppressor Genes; Undifferentiated; Variant; base; cell transformation; chemical carcinogen; combat; congenital cataract; cytokine; design; functional loss; heat shock transcription factor; in vivo; lens; mouse model; mutant mouse model; neoplastic cell; p19ARF; response; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): A hallmark in the pathogenesis of cancer is increased expression of heat shock proteins (Hsps) and other molecular chaperones; this is considered to be an adaptive response to enhanced tumor cell survival. Hsp expression is regulated at multiple levels, but heat shock transcription factors (Hsfs) are the primary regulators of stress-inducible expression in eukaryotic cells. Although the role of Hsf and Hsps in protecting organisms from a broad range of pathological conditions has been widely studied, their potential roles in malignancy are largely unexplored. Experimental evidence from our laboratory and others have uncovered in mouse models a surprising and critical role of Hsf1 is tumorigenesis. However, the contribution of other Hsfs, such as Hsf4, in oncogenesis remains elusive. During the last funding period of this grant, we created hsf4-/- mice to study its physiological function in vivo. We interestingly discovered that an Hsf4-mediated response plays a critical role in tumor growth and progression: Intriguingly, this response differentially impacts the tumorigenesis by either supporting or inhibiting tumor growth, depending on the model under investigation. In this grant utilizing our mutant mice models we will critically evaluate the following hypothesis: The opposing effects of Hsf4 in oncogenesis reflects its prominent function in orchestrating a network of cellular functions, including promotion of myoblast cell differentiation, which preferentially inhibits rhabdomyosarcomas (RMS) development as well as modulating tumor microenvironment components that enhance hepatocellular carcinoma (HCC) initiation and progression. We propose to pursue the following specific aims: Aim I. To investigate how hsf4 control of cellular differentiation impacts tumorigenesis in mouse models of spontaneous tumorigenesis. Aim II. To investigate how hsf4 control of cellular differentiation and the microenvironment impacts tumorigenesis in mouse models of a chemical-induced cancer. Aim III. To investigate Hsf4 expression and function in human RMS cell lines and primary tumors. The proposed studies will help to achieve a better understanding of the fundamental cellular processes in which Hsfs and general molecular chaperones engage to promote tumor growth, and may help to develop strategies to modulate specific chaperone-dependent host pathways as a therapeutic approach to combat human cancers and other relevant diseases. PUBLIC HEALTH RELAVANCE: The heat shock transcription factor Hsf4 exhibits properties of a tumor suppressor gene and its functional loss is associated with acceleration of tumorigenesis demonstrated in mouse models. The fact that Hsf4 expression is also lost in human tumors; it is our proposal that Hsf4 loss may promote tumorigenesis in human.

描述(申请人提供)：癌症发病机制的一个标志是热休克蛋白(HSPs)和其他分子伴侣蛋白的表达增加；这被认为是对提高肿瘤细胞存活率的适应性反应。在真核细胞中，HSP的表达受到多种水平的调控，但热休克转录因子(Hsf)是应激诱导表达的主要调节因子。尽管HSF和HSPs在保护生物体免受广泛的病理条件影响方面的作用已经被广泛研究，但它们在恶性肿瘤中的潜在作用在很大程度上还没有被探索。我们实验室和其他实验室的实验证据已经在小鼠模型中发现了HSF1令人惊讶的和关键的作用是肿瘤发生。然而，其他Hsf，如HSF4，在肿瘤发生中的作用仍然难以捉摸。在这笔赠款的最后一次资助期间，我们创造了HSF4-/-小鼠来研究其在体内的生理功能。我们有趣地发现，HSF4介导的反应在肿瘤的生长和进展中起着关键作用：有趣的是，这种反应通过支持或抑制肿瘤生长而不同地影响肿瘤的发生，这取决于所研究的模型。在这项利用我们的突变小鼠模型的拨款中，我们将批判性地评估以下假设：HSF4在肿瘤发生中的相反作用反映了其在协调一系列细胞功能方面的突出功能，包括促进成肌细胞分化，优先抑制横纹肌肉瘤(RMS)的发展以及调节促进肝细胞癌(HCC)启动和进展的肿瘤微环境成分。我们建议追求以下特定的目标：目的1.研究HSF4对细胞分化的控制如何影响自发肿瘤发生的小鼠模型的肿瘤发生。目的II.研究HSF4对细胞分化和微环境的控制如何影响化学致癌小鼠模型的肿瘤发生。目的III.研究热休克蛋白4(HSF4)在人RMS细胞系和原发肿瘤中的表达和功能。拟议的研究将有助于更好地了解Hsf和普通分子伴侣参与促进肿瘤生长的基本细胞过程，并可能有助于制定策略，调节特定的伴侣依赖宿主途径，作为对抗人类癌症和其他相关疾病的治疗方法。公共卫生相关性：热休克转录因子HSF4表现出肿瘤抑制基因的特性，其功能丧失与小鼠模型中肿瘤形成的加速有关。事实上，HSF4在人类肿瘤中也表达缺失；我们认为HSF4缺失可能促进人类肿瘤的发生。