Suppression of mobile elements by p53 genes

p53 基因对移动元件的抑制

• 批准号: 8942424
• 负责人: John M Abrams
• 金额: $ 31.9万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8942424
• 关键词: Alleles; Animals; Apoptosis; Automobile Driving; Biological Markers; Biology; Biosensor; Cancer Etiology; Cancer Patient; Deltastab; Disabled Persons; Disease; Drosophila genus; Elements; Employee Strikes; Engineering; Exposure to; Family; Gene Family; Gene Targeting; Generations; Genes; Genetic Complementation Test; Genetic Models; Genome; Genome Stability; Genomics; Goals; Human; Human Pathology; Kinetics; Lesion; Link; Malignant Neoplasms; Mediating; Modeling; Movement; Mus; Mutant Strains Mice; Mutate; Mutation; Nature; Noxae; Outcome; Pathologic; Pathology; Pathway interactions; Positioning Attribute; Property; Puma; Reporting; Repression; Retrotransposon; Route; Sampling; Specific qualifier value; System; TP53 gene; Testing; Time; Tissues; To specify; Tumor Suppression; Variant; age related; base; biological adaptation to stress; fly; gene function; human disease; human tissue; improved; in vivo; insight; mouse model; mutant; novel; outcome forecast; piRNA; pressure; public health relevance; research study; response; tool; transcription factor; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): 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. However, despite extensive characterization, precisely how p53 acts to suppress tumors and mitigate age- related disease remains poorly 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 the Drosophila system. This genetic model offers uniquely powerful opportunities for interrogating conserved networks that support human pathologies and, like its mammalian counterparts, the Drosophila p53 gene specifies adaptive responses to damage that preserve genome stability. Leveraging experimental tools that visualize real-time p53 action in vivo, we discovered that p53 normally contains the activity of transposons, 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 normal human p53 genes can restrain transposons but mutated p53 alleles from cancer patients cannot. These combined discoveries suggest that p53 acts through highly conserved mechanisms to contain transposons. Furthermore, since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates disease 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 inspects the nature, scope and scale of transposon activity provoked by p53 lesions and elucidates mechanisms by which p53 acts to contain mobile elements. Within this framework, we examine whether p53 mutations are permissive for destabilized genomes and disease because they are permissive for deregulated transposons. Our approach integrates genetic models in flies and mice, together with curated human samples. 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 implicated in age-related diseases and firmly established in the etiology of cancers, these may, in turn, deliver new biomarkers that improve prognosis and inform tailored therapies.

 描述（由申请人提供）：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与年龄相关疾病有关，并在大多数人类癌症中发生改变。作为转录因子，p53基因介导靶点的选择性激活和抑制以指定适应性反应。然而，尽管有广泛的表征，p53如何精确地抑制肿瘤和减轻年龄相关疾病仍然知之甚少。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的功能，成为人类疾病的精神错乱。为了实现这一目标，我们正在探索果蝇系统中的p53调控网络。这种遗传模型提供了独特的强大的机会，询问保守的网络，支持人类的病理学和，像它的哺乳动物对应，果蝇p53基因指定的适应性反应，以保持基因组的稳定性损害。利用可视化体内实时p53作用的实验工具，我们发现p53通常含有转座子的活性，转座子是广泛涉及散发性和遗传性人类疾病的移动的元件。我们还发现，p53基因与皮尔纳途径相互作用，piRNA途径是一种古老且高度保守的途径，致力于抑制所有动物中的转座子。此外，通过将果蝇p53基因与人类p53基因的对应物交换，我们发现正常的人类p53基因可以抑制转座子，但来自癌症患者的突变p53等位基因不能。这些综合发现表明，p53通过高度保守的机制来包含转座子。此外，由于人类p53突变体不能进行这种活性，我们的研究结果提出了p53通过抑制转座子的运动来减轻疾病的可能性。与此一致，我们发现了p53突变小鼠和p53驱动的人类癌症中不受限制的逆转录转座子的初步证据。这一举措检查的性质，范围和规模的转座子活动引起的p53病变和阐明的机制，其中p53的行为包含移动的元素。在这个框架内，我们研究p53突变是否允许不稳定的基因组和疾病，因为它们允许去调节转座子。我们的方法整合了苍蝇和小鼠的遗传模型，以及精心策划的人类样本。从这一举措中出现的有价值的见解可能使新的分类器，使我们能够分层p53等位基因的基础上的属性，拮抗移动的元素。由于p53与年龄相关的疾病有关，并在癌症的病因学中牢固确立，因此这些可能反过来提供新的生物标志物，改善预后并为定制治疗提供信息。