Regulation and Function of Mammalian HSF4 in vivo

哺乳动物 HSF4 体内的调控和功能

基本信息

批准号：
8072719
负责人：
NAHID F MIVECHI
金额：
$ 25.76万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
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/8072719
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 Health 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 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

项目摘要

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（由申请人提供）：癌症发病机制的一个标志是热休克蛋白（Hsp）和其他分子伴侣的表达增加；这被认为是对增强肿瘤细胞存活的适应性反应。 Hsp 表达在多个水平上受到调节，但热休克转录因子 (Hsfs) 是真核细胞中应激诱导表达的主要调节因子。尽管 Hsf 和 Hsps 在保护生物体免受多种病理状况影响方面的作用已得到广泛研究，但它们在恶性肿瘤中的潜在作用很大程度上尚未被探索。我们实验室和其他实验室的实验证据在小鼠模型中发现，Hsf1 在肿瘤发生方面具有令人惊讶且关键的作用。然而，其他 Hsfs（例如 Hsf4）在肿瘤发生中的贡献仍然难以捉摸。在本次资助的最后一个资助期内，我们创建了 hsf4-/- 小鼠来研究其体内生理功能。有趣的是，我们发现 Hsf4 介导的反应在肿瘤生长和进展中发挥着关键作用：有趣的是，这种反应根据所研究的模型，通过支持或抑制肿瘤生长，对肿瘤发生产生不同的影响。在这项利用我们的突变小鼠模型的资助中，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细胞功能网络中的突出功能，包括促进成肌细胞分化，从而优先抑制横纹肌肉瘤（RMS）的发展以及调节肿瘤微环境成分，增强肝细胞癌（HCC）的发生和进展。我们建议追求以下具体目标：目标 I. 研究 hsf4 对细胞分化的控制如何影响自发性肿瘤发生的小鼠模型中的肿瘤发生。目标二。旨在研究 hsf4 对细胞分化和微环境的控制如何影响化学诱导癌症小鼠模型中的肿瘤发生。目标三。研究人类 RMS 细胞系和原发性肿瘤中 Hsf4 的表达和功能。拟议的研究将有助于更好地理解 Hsfs 和一般分子伴侣参与促进肿瘤生长的基本细胞过程，并可能有助于制定调节特定伴侣依赖性宿主途径的策略，作为对抗人类癌症的治疗方法以及其他相关疾病。公共健康相关性：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证实的肿瘤发生加速有关。事实上，Hsf4 表达在人类肿瘤中也缺失；我们认为Hsf4缺失可能促进人类肿瘤发生。