Cell lineage determinants of p53-driven fate outcomes in vivo

项目摘要 TP53基因突变在人类癌症中是常见的，野生型p53明显与肿瘤有关 抑制器。越来越多的证据支持肿瘤相关突变型p53不仅 失去了肿瘤抑制活性，但也获得了致癌作用。因此，一个核心的重大挑战是 为了阐明野生型p53和癌基因p53的肿瘤抑制功能的分子基础， 突变型p53的活性，以及解卷积这两者之间的分子关系。是合理 期望对野生型介导的肿瘤抑制的相关详细见解将有助于理解 突变体驱动的肿瘤发生，反之亦然。进一步假设，通过研究野生型和突变型p53， 与此同时，将获得否则难以获得的见解。进一步混淆了这个复杂的 问题，使用小鼠模型的体内研究表明，p53驱动的细胞命运结果，无论是肿瘤， 抑制或致癌的，可以是组织特异性的。虽然p53已被证明具有细胞质功能， 它在控制基因表达中的作用肯定是其野生型肿瘤抑制作用和 突变的致癌功能计划中的研究的目标是解决这一重大问题， 重要的翻译潜力。具体目标是探索组织特异性转录活性 野生型或突变型p53在体内的表达，并确定p53驱动的命运结果的谱系特异性决定因素 在组织的子集中，即肝脏、胸腺和脾脏。第一个目标集中在体内野生型p53， 涉及阐明细胞谱系的分子基础，作为野生型p53依赖性 DNA损伤的反应。第二个目的是研究肿瘤相关突变型p53， 突变型p53的组织特异性致癌活性的分子基础。鉴于转录的重要作用， p53活性的调节，推测下游控制特定靶基因是关键 细胞结果的决定因素。阐明野生型抗肿瘤活性的分子基础 p53对于能够利用这些发现作为在肿瘤细胞中恢复这种功能的手段是必不可少的， 治疗方法同样，肿瘤相关突变型p53的致癌活性增加， 为涉及肿瘤抑制因子的靶向治疗提供了意想不到的可能性。作为一个关键的区别， 正常细胞和肿瘤细胞之间的区别是它们的p53状态，预计这种方法可能具有 治疗指数高。鉴于对p53反应的组织特异性，研究p53驱动的 以细胞系依赖的方式处理命运结果，为拟议的 research.

PROJECT SUMMARY Mutation of the TP53 gene is frequent in human cancer with wild-type p53 clearly being implicated as a tumor suppressor. A growing body of evidence now supports the notion that tumor-associated mutant p53 has not only lost tumor suppressing activity, but has also gained oncogenic roles. Thus, a central and significant challenge is to elucidate the molecular bases both for the tumor suppressing functions of wild-type p53 and the oncogenic activities of mutant p53 as well as deconvoluting the molecular relationship between these two. It is reasonable to expect that relevant detailed insights into wild-type-mediated tumor suppression will inform understanding of mutant-driven oncogenesis and vice versa. It is further hypothesized that by studying wild-type and mutant p53 in parallel, insights will be gained that would have been otherwise elusive. Further confounding this complex question, studies using mouse models in vivo indicate that p53-driven cell fate outcomes, be they tumor suppressing or oncogenic, can be tissue-specific. Although p53 has been shown to have cytoplasmic functions, its role in controlling gene expression is certainly central to both its wild-type tumor suppressing role and its mutant oncogenic function. The goal of the planned studies is to address this significant issue which carries important translational potential. Specific aims are proposed to explore the tissue-specific transcriptional activity of either wild-type or mutant p53 in vivo and to identify lineage-specific determinants for p53-driven fate outcomes in a subset of tissues, namely, liver, thymus, and spleen. The first aim is focused on wild-type p53 in vivo and involves elucidating the molecular basis for cell lineage as a determinant for the wild-type p53-dependent response to DNA damage. The second aim deals with tumor-associated mutant p53 and is to explore the molecular basis for the tissue-specific oncogenic activity of mutant p53. Given the essential role of transcriptional regulation in the activity of p53, it is postulated that downstream control of specific target genes are key determinants of cellular outcomes. Elucidating the molecular basis for the tumor suppressor activity of wild-type p53 is essential to be able to exploit such findings as a means to restore this function in tumor cells as a therapeutic approach. Likewise, the existence of gained oncogenic activity by tumor-associated mutant p53 provides the unexpected possibility for a targeted therapy involving a tumor suppressor. As a key difference between normal and tumor cells is their p53 status, it is anticipated that such approaches are likely to have a high therapeutic index. Given the tissue-specificity of responses to p53, it is essential that studies of p53-driven fate outcomes be addressed in a cell lineage-dependent manner, providing a central tenet for the proposed research.