Tissue-specific tumor suppressor effects of p53

 描述(申请人提供)：肿瘤抑制基因P53被认为在人类癌症中起关键作用。P53作为一种转录因子在很大程度上发挥了其活性，调节了有助于抑制肿瘤形成的基因表达。它的C末端与组蛋白尾巴有显著的相似性。两者都富含碱性氨基酸 这两本书都经过了广泛的翻译后修改。与组蛋白尾巴一样，P53的C末端可以被认为是一个蛋白质-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。为了阐明P53的C-末端在其活性中的作用，在小鼠中进行了定向突变，导致内源性表达缺失C-末端24个氨基酸的截短形式的P53。当P53∆CTD在生殖系中表达时，小鼠表现出两种明显的表型：导致严重贫血的造血干细胞数量减少，以及导致小脑发育缺陷和共济失调的颗粒细胞增殖受损。潜在的分子基础涉及组织特异性的p53靶基因选择和表达的改变。这些表型惊人的组织特异性是意想不到的，也非常耐人寻味。此外，对TrP53∆CTD/∆CTD小鼠的研究还导致了新的组织特异性P53靶基因的鉴定。鉴于p53具有如此强大的肿瘤抑制活性，推测这一点可能被作为一种理性的 作为靶向治疗的基础。然而，显然无处不在的P53表达表明，很难达到有效的治疗指数。对TrP53∆CTD/∆CTD小鼠的研究结果表明，P53的C末端结构域以目标基因选择性的方式发挥组织特异性效应。因此，有人提出，干扰P53的C-末端结构域的功能可以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。一是阐明P53介导的骨髓衰竭中C-末端结构域的分子基础。二是确定P53 C末端结构域在小脑颗粒细胞动态平衡和肿瘤发生中的作用。最后，从分子水平深入了解P53 C-末端结构域如何调节激活的P53信号。由于C末端被认为是一个蛋白质-蛋白质相互作用模块，因此抑制C末端的蛋白质相互作用代表了一种针对特定肿瘤类型的新的靶向治疗。因此，这些研究的长期目标是使用活体小鼠模型来获得对p53在白血病和髓母细胞瘤中的作用的新见解，并为这些疾病的靶向治疗提供新的方法。

 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.