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.

项目摘要 TP53基因的突变在人类癌症中经常存在，野生型p53显然被视为肿瘤 抑制器。现在，越来越多的证据支持以下观点：肿瘤相关突变体p53不仅具有 失去抑制肿瘤活性，但也发挥了致癌作用。因此，一个核心和重大挑战是 为了阐明野生型p53和致癌功能的肿瘤抑制功能的分子碱基 突变体p53的活性以及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相关的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体P53 同时，将获得洞察力，这本来是难以捉摸的。进一步混淆了这个复合物 问题，使用小鼠模型在体内的研究表明p53驱动的细胞命运结果，无论是肿瘤 抑制或致癌性可能是组织特异性的。尽管p53已显示具有细胞质功能，但 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及其的核心 突变的致癌功能。计划研究的目的是解决这个重大问题，该问题带有 重要的翻译潜力。提出了具体目的来探索组织特异性的转录活性 野生型或突变体p53体内，并确定p53驱动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。第一个目的是专注于体内野生型p53和 涉及阐明细胞谱系的分子基础作为野生型p53依赖性的决定因素 对DNA损伤的反应。第二个目标涉及与肿瘤相关的突变体P53，并探索 突变体p53组织特异性致癌活性的分子基础。鉴于转录的基本作用 p53活性的调节，据推测，特定靶基因的下游控制是关键 细胞结局的决定因素。阐明野生型肿瘤抑制活性的分子基础 p53对于能够利用此类发现是一种将肿瘤细胞中此功能恢复此功能的手段至关重要的 治疗方法。同样，存在与肿瘤相关的突变体p53获得的致癌活性 为涉及肿瘤抑制剂的靶向疗法提供了意外的可能性。作为关键区别 在正常和肿瘤细胞之间是其p53状态，预计这种方法可能具有 高治疗指数。鉴于对p53的响应的组织特异性，必须进行p53驱动的研究 命运结果以细胞谱系的方式解决，为提议提供了中心宗旨 研究。