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（由适用提供）：整个动物王国的压力反应网络中的p53基因家族职业中心位置。在人类中，p53隐含在与年龄有关的疾病中，并在大多数人类癌症中改变。作为转录因子，p53基因的中位数选择性激活和靶标表达以指定自适应反应。然而，dospite广泛的特征，正是p53如何作用抑制肿瘤并减轻与年龄相关的疾病的理解率还不佳。由于p53基因是广泛保守的，因此这些基因的祖先特性为理解p53的功能而在人类疾病中被危险的功能提供了承诺的途径。为了实现这一目标，我们正在探索果蝇系统中的p53监管网络。这种遗传模型为审问支持人类病理的保守网络提供了独特的机会，并且像其哺乳动物对应物一样，果蝇p53基因指定了对保留基因组稳定性损害的适应性反应。利用可视化实时p53动作的实验工具，我们发现p53通常包含转座的活性，盆腔的活性是在弹性和可遗传的人类疾病中广泛暗示的移动元素。我们还表明，P53与PiRNA途径相互作用，PiRNA途径是一种古老而高度保守的途径，致力于抑制所有动物的转座子。此外，通过将苍蝇p53基因与人p53同类交换，我们发现正常的人p53基因可以抑制转座子，但是癌症患者的突变p53等位基因不能。这些结合发现表明，p53通过高度组成的机制起作用以包含转座子。此外，由于人类p53突变体因这种活动而被禁用，因此我们的发现增加了p53通过抑制转座子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驱动的人类癌症中无情的逆转录子的初步证据。该倡议检查了p53病变引起的转座子活动的性质，范围和尺度，并阐明了p53通过这些机制来包含移动元件的机制。在此框架内，我们检查了p53突变是否允许对不稳定的基因组和疾病，因为它们允许进行放松管制的转座子。我们的方法将果蝇和小鼠中的遗传模型与精选的人类样品一起整合。这项计划从该计划中产生的有价值的见解可以使新的分类器使我们能够根据对移动元素的属性进行分层p53等位基因。由于p53是在与年龄有关的疾病中实施的，并首先在癌症的病因中建立，因此这些疾病可能会提供新的生物标志物，以改善预后并为量身定制的疗法提供信息。