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anti-tumor activity of deacetylase inhibitors

脱乙酰酶抑制剂的抗肿瘤活性

基本信息

批准号：
7359670
负责人：
MARIA L AVANTAGGIATI
金额：
$ 27.15万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-08 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7359670
关键词：
Ablation Acetylation Acetyltransferase Address Affect Alleles Animal Model Animals Apoptosis Cell Cycle Arrest Cell Line Cells Chemoprotection Colorectal Cancer Complex DNA Binding DNA Damage Data Deacetylase Deacetylation Development Disease Enzymes Estrogens Event Excision Frequencies Gene Expression Regulation Genes Genetic Transcription Goals High Dose Chemotherapy Histone Deacetylase Histones Impairment Individual Lead Lysine Malignant - descriptor Malignant Neoplasms Missense Mutation Molecular Molecular Mechanisms of Action Mus Mutation Normal Cell Numbers Oncogenes Oncogenic Outcome PCAF acetylase PCAF gene Pathogenesis Pathway interactions Patients Peptides Personal Satisfaction Phase I Clinical Trials Play Positioning Attribute Post-Translational Protein Processing Protein p53 Proteins Purpose Regulation Repression Resistance Role Site TP53 gene Testing Therapeutic Transcriptional Activation Transgenic Animals Transgenic Mice Work antitumor agent base cancer type cell growth cell growth regulation cell killing cell type chemotherapeutic agent chemotherapy cytotoxicity design functional restoration genetic manipulation human GATA1 protein in vivo inhibitor/antagonist mouse model mutant neoplastic cell novel response success transcription factor tumor tumorigenesis

项目摘要

The goal of this application is to study the molecular mechanisms underlying the anti-tumor activity of inhibitors of deacetylase enzymes (HDACs). These enzymes, which catalyze the removal of an acetyl group from the lysine residues of proteins, are well recognized to play an important role in the regulation of gene expression, and have also been implicated in malignant transformation. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that block proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. Quite surprisingly, the effects of HDAC inhibitors seem to be somewhat selective for tumor cells and several of these compounds have now entered phase I clinical trials. From a molecular point of view, HDAC inhibition not only results in hyperacetylation of histones but also of key transcription factors such as p53, GATA-1 and estrogen receptoralpha. However thus far, the functional significance of acetylation of non-histone proteins in regulation of cell growth, and the precise mechanisms through which HDAC inhibitors induce tumor cell growth arrest remain poorly understood. We have now identified the p53 gene product as a major determinant of sensitivity to these agents, though in an unexpected way. We found that cells harboring mutations of the p53 gene, which generally confer resistance to treatment with canonical chemotherapeutic agents, are sensitive to the action of the HDAC inhibitor, TSA. We provide evidence that inhibition of HDACs, via TSA treatment, restores function from several types of p53 mutants at least in part due to p53 acetylation, and thus promotes apoptosis. By contrast, in the case of wild-type p53 acetylation of a particular residue, Lysine 320, confers chemo-protection. Based on these data we hypothesize that acetylation differentially influences the activity of wild-type and mutant forms of p53. To address this issue we will take advantage of mice genetically modified in components of the acetylation and of the p53 pathway, of unique cell types, and of a panel of p53 proteins harboring mutations at the known acetylation sites. Furthermore, we propose to identify the cellular deacetylase(s) that targets K320 and to exploit acetylation of this residue for therapeutic purposes. We expect that these studies will generate important information on the pathogenesis of cancer disease, and will provide new leads for the therapy of many types of cancer.

本应用程序的目的是研究脱乙酰酶抑制剂（HDACs）抗肿瘤活性的分子机制。这些酶催化蛋白质赖氨酸残基上乙酰基的去除，在基因表达调控中发挥重要作用，也与恶性转化有关。近年来，越来越多的结构多样的HDAC抑制剂被发现可以在培养和动物模型中阻断肿瘤细胞的增殖，诱导肿瘤细胞分化和/或凋亡。令人惊讶的是，HDAC抑制剂的作用似乎对肿瘤细胞具有一定的选择性，其中一些化合物现在已经有了