Cell lineage determinants of p53-driven fate outcomes in vivo

p53驱动的体内命运结果的细胞谱系决定因素

• 批准号: 10538642
• 负责人: James J Manfredi
• 金额: $ 57.65万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-09 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538642
• 关键词: Address; Apoptosis; Cell Lineage; Cells; Complex; Cytoplasm; DNA Damage; Diagnosis; Gene Expression; Genes; Genetic Transcription; Goals; Human; Knowledge; Liver; Malignant Neoplasms; Mediating; Molecular; Mutation; Normal Cell; Oncogenic; Outcome; Radiation Tolerance; Research; Resistance; Role; Specificity; Spleen; TP53 gene; Therapeutic; Therapeutic Index; Thymus Gland; Tissue-Specific Gene Expression; Tissues; Transcriptional Regulation; Tumor Suppression; Tumor Suppressor Proteins; Tumor-Derived; base; design; functional restoration; gain of function; improved; in vivo; in vivo Model; insight; mouse model; mutant; neoplastic cell; new therapeutic target; response; targeted treatment; translational potential; tumor; tumorigenesis

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.

项目概要 TP53 基因突变在人类癌症中很常见，野生型 p53 显然与肿瘤有关 抑制器。现在越来越多的证据支持肿瘤相关突变 p53 不仅具有 失去了肿瘤抑制活性，但也获得了致癌作用。因此，一个核心且重大的挑战是 阐明野生型 p53 和致癌基因的肿瘤抑制功能的分子基础 突变体 p53 的活性以及解开这两者之间的分子关系。这是合理的 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 同时，还将获得原本难以捉摸的见解。进一步混淆了这个复合体 问题，使用小鼠体内模型的研究表明，p53 驱动的细胞命运结果，无论是肿瘤还是肿瘤 抑制或致癌，可以是组织特异性的。尽管p53已被证明具有细胞质功能， 它在控制基因表达方面的作用无疑是其野生型肿瘤抑制作用及其 突变的致癌功能。计划研究的目标是解决这一重大问题 重要的转化潜力。提出了探索组织特异性转录活性的具体目标 体内野生型或突变型 p53 的分析，并确定 p53 驱动的命运结果的谱系特异性决定因素 在一部分组织中，即肝脏、胸腺和脾脏。第一个目标是体内野生型p53 涉及阐明细胞谱系作为野生型 p53 依赖性决定因素的分子基础 对DNA损伤的反应。第二个目标涉及肿瘤相关突变体 p53，并探索 突变体 p53 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，推测特定靶基因的下游控制是关键 细胞结果的决定因素。阐明野生型肿瘤抑制活性的分子基础 p53 对于能够利用这些发现作为恢复肿瘤细胞中这种功能的手段至关重要。 治疗方法。同样，肿瘤相关突变体 p53 获得致癌活性的存在 为涉及肿瘤抑制剂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在于它们的 p53 状态，预计这种方法可能具有 治疗指数高。鉴于 p53 反应的组织特异性，对 p53 驱动的研究至关重要 命运结果以细胞谱系依赖的方式得到解决，为拟议的 研究。