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被认为在人类癌症中起关键作用。p53发挥其作为调节基因表达的转录因子的大部分活性，所述基因表达有助于抑制肿瘤形成。它的C-末端与组蛋白尾部的C-末端具有显著的相似性。两者都富含碱性氨基酸 两者都经过了广泛的后期修饰。与组蛋白尾部一样，p53的C-末端可以被认为是蛋白质-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的C-末端在其活性中的作用，在小鼠中进行靶向突变，其导致缺乏C-末端24个氨基酸的截短形式的p53的内源性表达。当p53 β CTD在生殖系中表达时，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和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。这些表型的显著组织特异性是出乎意料的，并且非常有趣。此外，对Trp 53 β CTD/β CTD小鼠的研究已经鉴定出新的组织特异性p53靶基因。考虑到p53具有如此强大的肿瘤抑制活性，推测这可能被用作合理的治疗方法是有趣的。 靶向治疗的基础。然而，p53的明显普遍表达表明难以实现有效的治疗指数。Trp 53 β CTD/β CTD小鼠的发现表明，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的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介导的骨髓衰竭的C-末端结构域的分子基础。第二是确定p53 C端结构域在小脑颗粒细胞稳态和肿瘤发生中的作用。最后，是获得分子洞察如何p53的C-末端结构域调节激活p53信号。由于C-末端已被很好地表征为蛋白质-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中的新型靶向疗法。因此，这些研究的长期目标是使用体内小鼠模型来获得对p53在白血病和髓母细胞瘤中的作用的新见解，以及为这些疾病的靶向治疗提供新方法。