Tissue-specific tumor suppressor effects of p53

p53 的组织特异性肿瘤抑制作用

• 批准号: 9112967
• 负责人: James J Manfredi
• 金额: $ 41.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-17 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112967
• 关键词: Address; Amino Acids; Anemia; Ataxia; Basic Amino Acids; Bone Marrow; C-terminal; DNA Damage; Data; Development; Disease; Embryo; Employee Strikes; Fibroblasts; GFI1 gene; GFI1B gene; Gene Expression; Gene Targeting; Genes; Germ Lines; Goals; Health; Hematopoietic stem cells; Histones; Homeostasis; Human; Knowledge; Malignant Neoplasms; Mediating; Mind; Molecular; Mus; Mutation; Outcome; Pancytopenia; Phenotype; Play; Protein p53; Proteins; Research; Role; Signal Transduction; Specificity; TP53 gene; Tail; Therapeutic Index; Tissues; Transcriptional Regulation; Tumor Suppression; Tumor Suppressor Proteins; Ursidae Family; base; diagnosis design; granule cell; improved; in vivo; insight; leukemia; medulloblastoma; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; protein protein interaction; recombinase; response; targeted treatment; transcription factor; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): The tumor suppressor p53 has been implicated as playing a key role in human cancer. p53 exerts much of its activity as a transcription factor that regulates gene expression that contributes to the suppression of tumor formation. Its C-terminus bears remarkable similarity to that of histone tails. Both are highly enriched in basic amino acids and both are extensively post-translationally modified. Like histone tails, the C-terminus of p53 can be considered a protein-protein interaction module. This in turn regulates its activity as a transcription factor. To address the role of the C-terminus of p53 in its activity, a targeted mutation was made in the mouse that leads to endogenous expression of a truncated form of p53 that lacks the C-terminal 24 amino acids. When p53∆CTD is expressed in the germ-line, mice show two overt phenotypes: a reduced number of hematopoietic stem cells leading to severe anemia and impaired proliferation of granule cells resulting in defective cerebellar development and ataxia. The underlying molecular basis involves tissue-specific alterations in p53 target gene selection and expression. The striking tissue specificity of these phenotypes was unexpected and quite intriguing. In addition, study of the Trp53∆CTD/∆CTD mice has led to the identification of novel, tissue-specific p53 target genes. Given that p53 has such potent tumor suppressor activity, it is intriguing to speculate that this might be exploited as a rational basis for targeted therapy. However, the apparently ubiquitous expression of p53 suggests that it would be difficult to achieve an effective therapeutic index. Findings with Trp53∆CTD/∆CTD mice demonstrate that the C-terminal domain of p53 exerts tissue- specific effects in a target gene-selective manner. It is thus proposed that interfering with the function of the C- terminal domain of p53 can be utilized for targeted therapy that is highly tumor-specific. With that long-term goal in mind, three specific aims are proposed. The first is to elucidate the molecular basis for the C-terminal domain in p53-mediated bone marrow failure. Second is to determine the role of the p53 C-terminal domain in cerebellar granule cell homeostasis and tumorigenesis. Finally, is to gain molecular insight into how the p53 C- terminal domain regulates activated p53 signaling. As the C-terminus has been well characterized as a protein- protein interaction module, it is proposed that inhibiting the protein interactions of the C-terminus represents a novel targeted therapy in specific tumor types. Thus, the long-term goal of these studies is to use in vivo mouse models to gain novel insights into the role of p53 in leukemia and medulloblastoma, as well as to provide new approaches for targeted therapies in these diseases.

 描述（由申请人提供）：肿瘤抑制因子 p53 已被认为在人类癌症中发挥着关键作用。 p53 作为转录因子发挥其大部分活性，调节有助于抑制肿瘤形成的基因表达。它的 C 末端与组蛋白尾部非常相似。两者都富含碱性氨基酸 并且两者都经过广泛的翻译后修饰。与组蛋白尾部一样，p53 的 C 末端可被视为蛋白质-蛋白质相互作用模块。这反过来又调节其作为转录因子的活性。为了解决 p53 C 末端在其活性中的作用，在小鼠中进行了靶向突变，导致缺乏 C 末端 24 个氨基酸的 p53 截短形式的内源表达。当 p53ΔCTD 在种系中表达时，小鼠表现出两种明显的表型：造血干细胞数量减少导致严重贫血，颗粒细胞增殖受损导致小脑发育缺陷和共济失调。潜在的分子基础涉及 p53 靶基因选择和表达的组织特异性改变。这些表型的惊人组织特异性是出乎意料且非常有趣的。此外，对 Trp53ΔCTD/ΔCTD 小鼠的研究导致了新型组织特异性 p53 靶基因的鉴定。鉴于 p53 具有如此强大的肿瘤抑制活性，有趣的是推测这可能被用作合理的 为靶向治疗奠定基础。然而，p53 明显无处不在的表达表明很难达到有效的治疗指数。 Trp53ΔCTD/ΔCTD 小鼠的研究结果表明，p53 的 C 末端结构域以靶基因选择性方式发挥组织特异性作用。因此提出干扰p53 C末端结构域的功能可用于高度肿瘤特异性的靶向治疗。考虑到这一长期目标，提出了三个具体目标。第一个是阐明 p53 介导的骨髓衰竭中 C 末端结构域的分子基础。其次是确定 p53 C 末端结构域在小脑颗粒细胞稳态和肿瘤发生中的作用。最后，是从分子角度深入了解 p53 C 末端结构域如何调节激活的 p53 信号传导。由于 C 末端已被充分表征为蛋白质-蛋白质相互作用模块，因此提出抑制 C 末端的蛋白质相互作用代表了特定肿瘤类型的新型靶向治疗。因此，这些研究的长期目标是利用体内小鼠模型来深入了解p53在白血病和髓母细胞瘤中的作用，并为这些疾病的靶向治疗提供新方法。