Regulation of Mutant P53 Expression and Oncogenic Activity

突变 P53 表达和致癌活性的调节

• 批准号: 8520202
• 负责人: Xinbin Chen
• 金额: $ 26.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/8520202
• 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

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的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，并聚集在中央DNA结合结构域中。突变体p53在序列特异性DNA结合和生长抑制中有缺陷，这定义了功能突变的经典丧失。此外，具有完整域的四聚体p53是主要负的，因为突变体可以形成具有野生型p53的异驱动器。此外，突变体p53获得了额外的活性，称为功能增益。突变体p53功能增益在携带一个无效等位基因和一个突变等位基因（R172H或R270H）的敲门小鼠中概括。与p53-null小鼠相比，这些敲门蛋白小鼠会发展出侵略性肿瘤。最近，我们和其他人表明，携带突变体p53的肿瘤细胞沉迷于突变体，以生存和抵抗DNA损伤。因此，突变体p53的致癌特性为靶向突变体p53提供了癌症治疗的基本原理，包括将突变体重新激活到野生型的样子。然而，大量的p53突变（> 2,314种突变;：//www-p53.iarc.fr）提出了开发多功能p53反应药物的主要挑战，尤其是考虑到需要修改和/或物理相互作用来将突变体转化为野生型野生型野生型。此外，许多p53突变体稳定后，与其他p53家族肿瘤抑制剂相关并抑制（即p63和p73），然后会增强这些p53突变体的功能增益。因此，我们假设靶向突变体p53表达是沉迷于突变体p53的肿瘤的可行治疗策略。为了进一步解决这一问题，提出了三个具体目标：（1）确定突变体p53表达如何通过组蛋白脱乙酰基酶（HDACS）（尤其是HDAC8）转录调节，尤其是HDAC8以及HDAC8调节突变体p53表达的生物学意义； （2）确定突变体p53表达的RNPC1调节的生物学意义，以及在携带突变体p53的人肿瘤中是否抑制了RNPC1表达； （3）确定突变体p53蛋白稳定性如何受砷调节，以及砷是否可以抑制突变体p53诱导的细胞转化和肿瘤进展。