Tumor suppression, p53 and retrotransposons

肿瘤抑制、p53 和逆转录转座子

• 批准号: 9978740
• 负责人: John M Abrams
• 金额: $ 37.06万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978740
• 关键词: Alleles; Animals; Apoptosis; Automobile Driving; Biological Markers; Biology; Cancer Etiology; Cancer Model; Cancer Patient; Clinic; Complement; Deltastab; Disabled Persons; Disease; Elements; Family; Family member; Fishes; Gene Family; Genes; Genetic Models; Genome; Genome Stability; Goals; Heritability; Human; Human Pathology; Lesion; Link; Malignant Neoplasms; Mediating; Modeling; Molecular; Movement; Mus; Mutant Strains Mice; Mutate; Mutation; Oncogenic; Pathway interactions; Positioning Attribute; Property; Reporting; Repression; Retroelements; Retrotransposon; Role; Route; Specific qualifier value; System; TP53 gene; Testing; Time; To specify; Tumor Suppression; Zebrafish; age related; base; biological adaptation to stress; fly; gene function; human disease; in vivo; innovation; insight; member; mutant; novel; novel therapeutics; piRNA; preservation; pressure; prevent; response; support network; tool; transcription factor; tumor; tumorigenesis

Project Summary The p53 gene family occupies central positions in stress response networks throughout the animal kingdom. In humans p53 is implicated in age-related diseases and altered in most human cancers. As transcription factors, p53 genes mediate selective activation and repression of targets to specify adaptive responses but, despite extensive characterization, precisely how p53 acts to suppress tumors is not well understood. Since p53 genes are broadly conserved, ancestral properties of these genes offer promising routes towards understanding functions of p53 that become deranged in human diseases. Toward this goal, we are exploring the p53 regulatory network in genetic models. These systems offer uniquely powerful opportunities for interrogating conserved networks that support human pathologies. For example, like mammalian counterparts, p53 genes in flies and fish specify adaptive responses to damage that preserve genome stability. Leveraging experimental tools that visualize real-time p53 action in vivo, we discovered that p53 normally restrains retrotransposons, which are mobile elements broadly implicated in sporadic and heritable human disease. We also showed that p53 genetically interacts with the piRNA pathway, an ancient and highly conserved pathway dedicated to the suppression of transposons in all animals. In addition, by exchanging the fly p53 gene with human p53 counterparts, we found that human p53 genes could similarly restrain transposons but mutated p53 alleles from cancer patients could not. These combined discoveries suggest that p53 acts through highly conserved mechanisms to repress transposons. Furthermore, since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates cancer by suppressing the movement of transposons. Consistent with this, we uncovered preliminary evidence for unrestrained retrotransposons in p53 mutant mice and in p53-driven human cancers. This initiative will determine how p53 acts to contain mobile elements and inspects these properties in other human members of the p53 gene family. Within this framework, we also determine whether p53 mutations are permissive for cancer because they are permissive for deregulated transposons. Our approach integrates molecular systems in flies and zebrafish, together with models of p53-driven tumors in mice. Valuable insights emerging from this initiative may enable novel classifiers that permit us to stratify p53 alleles based on properties that antagonize mobile elements. Since p53 is firmly established in the etiology of cancers these insights may, in turn, deliver new biomarkers and inform new therapeutic opportunities.

项目摘要 p53基因家族在整个动物界的应激反应网络中占据中心位置。 在人类中，p53与年龄相关的疾病有关，并在大多数人类癌症中发生改变。如转录 因子，p53基因介导靶的选择性激活和抑制以指定适应性反应，但是， 尽管进行了广泛的表征，但p53如何精确地抑制肿瘤还没有很好地理解。 由于p53基因是广泛保守的，这些基因的祖先特性提供了有希望的途径， 了解p53在人类疾病中的功能。为了实现这一目标，我们 探索遗传模型中的p53调控网络。这些系统提供了独特的强大功能， 询问支持人类病理学的保守网络的机会。比如像 在哺乳动物中，果蝇和鱼类中的p53基因指定了对破坏的适应性反应， 基因组稳定性利用可视化实时p53在体内作用的实验工具，我们发现 p53通常抑制反转录转座子，反转录转座子是移动的元件，广泛涉及零星和 遗传性人类疾病我们还表明，p53基因与皮尔纳途径相互作用， 这是一条古老且高度保守的途径，致力于抑制所有动物中的转座子。在 此外，通过将果蝇p53基因与人p53基因进行交换，我们发现人p53基因 可以类似地抑制转座子，但来自癌症患者的突变的p53等位基因不能。这些 结合的发现表明p53通过高度保守的机制来抑制转座子。 此外，由于人类p53突变体不能进行这种活性，我们的发现提出了这样的可能性， p53通过抑制转座子的运动来减轻癌症。与此相一致，我们发现 p53突变小鼠和p53驱动的人类中无限制反转录转座子的初步证据 癌的这一举措将决定p53如何遏制移动的元素，并检查这些元素 p53基因家族的其他人类成员的特性。在此框架内，我们还确定 p53突变是否允许癌症，因为它们允许去调节的转座子。 我们的方法整合了苍蝇和斑马鱼的分子系统，以及p53驱动的 小鼠的肿瘤这一举措中出现的有价值的见解可能会实现新颖的分类器，使我们能够 基于拮抗移动的元件的特性对p53等位基因进行分层。由于p53在 癌症的病因学这些见解可能反过来提供新的生物标志物，并为新的治疗方法提供信息。 机会