Regulation of Mutant P53 Expression and Oncogenic Activity

突变 P53 表达和致癌活性的调节

基本信息

批准号：
8676449
负责人：
Xinbin Chen
金额：
$ 27.44万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676449
关键词：
Acute Promyelocytic Leukemia Address Adjuvant Alleles Antineoplastic Agents Arsenic Arsenic Trioxide Biological Cell Cycle Cell Proliferation Cell physiology Cells Chimeric Proteins DNA Binding DNA Binding Domain DNA Damage Dominant-Negative Mutation Embryo Family Fibroblasts Gene Expression Genetic Transcription Growth Hematologic Neoplasms Histone Deacetylase Inhibitor Histones Human Knockout Mice Lipid Peroxidation Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Missense Mutation Modification Mus Mutation Oncogenes Oncogenic Oxidative Stress Pathway interactions Pharmaceutical Preparations Property Protein p53 Proteins Public Health RNA-Binding Proteins Recruitment Activity Regulation Resistance Role Sampling Solid Neoplasm TP53 gene Therapeutic Translations Tumor Suppression Tumor Suppressor Proteins Tumor-Derived base cancer therapy carcinogenesis cell transformation gain of function inhibitor/antagonist insight loss of function mutation mutant neoplastic cell p53 Signaling Pathway tumor tumor progression ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Mutation of p53 is the most frequent genetic alteration in human cancer. The majority of tumor- derived p53 mutations is missense mutation and clustered within the central DNA-binding domain. Mutant p53 is defective in sequence-specific DNA binding and growth suppression, which defines the classical loss of function mutation. In addition, mutant p53 with an intact domain for tetramerization is dominant negative since the mutant can form a heterotetramer with wild-type p53. Moreover, mutant p53 acquires additional activity, called gain of function. Mutant p53 gain of function is recapitulated in knockn mice that carry one null allele and one mutant allele (R172H or R270H) of the p53 gene. These knockin mice develop aggressive tumors compared to p53-null mice. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for survival and resistance to DNA damage. Thus, the oncogenic properties of mutant p53 provide a rationale to target mutant p53 for cancer therapy, including the ones reactivating a mutant into wild-type-like. However, the large number of p53 mutations (> 2,314 types of mutations; ://www-p53.iarc.fr) poses a major challenge to develop versatile p53-reactivating drugs, especially considering that a modification and/or physical interaction is needed to convert a mutant into wild-type-like. Furthermore, a number of p53 mutants, when stabilized, associate with and inhibit other p53 family tumor suppressors (i.e., p63 and p73), which would then enhance gain of function for these p53 mutants. Thus, we hypothesize that targeting mutant p53 expression is a viable therapeutic strategy for tumors addicted to mutant p53. To further address this, three specific aims are proposed: (1) to determine how mutant p53 expression is transcriptionally regulated by histone deacetylases (HDACs), particularly HDAC8 and the biological significance of HDAC8 regulation of mutant p53 expression; (2) to determine the biological significance of RNPC1 regulation of mutant p53 expression and whether RNPC1 expression is suppressed in human tumors carrying a mutant p53; and (3) to determine how mutant p53 protein stability is regulated by arsenic and whether arsenic can suppress mutant p53-induced cell transformation and tumor progression.

描述（由申请人提供）：p53 突变是人类癌症中最常见的遗传改变。大多数肿瘤衍生的 p53 突变是错义突变，并且聚集在中央 DNA 结合域内。突变体 p53 在序列特异性 DNA 结合和生长抑制方面存在缺陷，这定义了经典的功能丧失突变。此外，具有完整四聚化结构域的突变体 p53 呈显性失活，因为该突变体可以与野生型 p53 形成异四聚体。此外，突变的 p53 获得了额外的活性，称为功能获得。突变体 p53 的功能获得在携带 p53 基因的一个无效等位基因和一个突变等位基因（R172H 或 R270H）的敲除小鼠中得到重现。与 p53 缺失小鼠相比，这些基因敲入小鼠会发展出侵袭性肿瘤。最近，我们和其他人证明，携带突变体 p53 的肿瘤细胞对突变体上瘾，以求生存和抵抗 DNA 损伤。因此，突变体 p53 的致癌特性为靶向突变体 p53 进行癌症治疗提供了理论依据，包括将突变体重新激活为野生型样的治疗。然而，大量的 p53 突变（> 2,314 种突变；://www-p53.iarc.fr）对开发多功能 p53 重新激活药物提出了重大挑战，特别是考虑到需要修饰和/或物理相互作用将突变体转化为野生型样。此外，许多 p53 突变体在稳定后，会与其他 p53 家族肿瘤抑制因子（即 p63 和 p73）结合并抑制，从而增强这些 p53 突变体的功能获得。因此，我们假设针对突变型 p53 表达是治疗突变型 p53 肿瘤的一种可行的治疗策略。为了进一步解决这个问题，提出了三个具体目标：（1）确定突变体p53表达如何被组蛋白脱乙酰酶（HDAC），特别是HDAC8转录调节，以及HDAC8调节突变体p53表达的生物学意义； (2)确定RNPC1调节突变型p53表达的生物学意义以及RNPC1表达在携带突变型p53的人类肿瘤中是否受到抑制； (3)确定砷如何调节突变型p53蛋白的稳定性以及砷是否可以抑制突变型p53诱导的细胞转化和肿瘤进展。