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.

本申请的目的是研究脱乙酰酶抑制剂 (HDAC) 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，被公认为在基因表达调节中发挥重要作用，并且还与恶性转化有关。近年来，越来越多的结构多样化的 HDAC 抑制剂被发现，可以在培养物和动物模型中阻断肿瘤细胞的增殖并诱导肿瘤细胞的分化和/或凋亡。非常令人惊讶的是，HDAC 抑制剂的作用似乎对肿瘤细胞具有一定的选择性，并且其中一些化合物现已进入I期临床试验。从分子角度来看，HDAC 抑制不仅导致组蛋白的过度乙酰化，以及 p53、GATA-1 和雌激素受体 α 等关键转录因子的过度乙酰化。然而到目前为止，非组蛋白乙酰化在调节中的功能意义细胞生长，以及 HDAC 抑制剂诱导肿瘤细胞生长停滞的精确机制仍知之甚少。我们现在已经确定 p53 基因产物是对这些药物敏感性的主要决定因素，尽管是以一种意想不到的方式。我们发现，携带 p53 基因突变的细胞对 HDAC 抑制剂 TSA 的作用敏感，该突变通常会对经典化疗药物产生耐药性。我们提供的证据表明，通过 TSA 处理抑制 HDAC，可以恢复几种类型的 p53 突变体的功能（至少部分是由于 p53 乙酰化），从而促进细胞凋亡。相比之下，在野生型 p53 特定残基赖氨酸 320 乙酰化的情况下，赋予化学保护。基于这些数据，我们假设乙酰化对 p53 野生型和突变型的活性有不同的影响。为了解决这个问题，我们将利用对乙酰化和 p53 通路成分进行基因改造的小鼠、独特的细胞类型以及一组在已知乙酰化位点含有突变的 p53 蛋白。此外，我们建议鉴定靶向 K320 的细胞脱乙酰酶，并利用该残基的乙酰化用于治疗目的。我们期望这些研究将产生有关癌症疾病发病机制的重要信息，并为多种癌症的治疗提供新的线索。