Polypoid cell cycle regulation and genome instability

息肉样细胞周期调控和基因组不稳定性

• 批准号: 10165740
• 负责人: BRIAN R CALVI
• 金额: $ 31.85万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-12 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165740
• 关键词: Address; Affect; Aneuploid Cells; Aneuploidy; Apoptosis; Apoptotic; Back; Binding; Biochemical Genetics; Biological; Biological Process; Blood; CDC2 gene; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell Size; Cell Survival; Cell division; Cells; Cellular Stress; Chromatin; Chromosomal Instability; Competence; Cycas; DNA; DNA Damage; Data; Development; Disease; Drosophila genus; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Genomic Instability; Genotoxic Stress; Growth; Health; Heart; Human; Knowledge; Lead; Link; Liver; MYB gene; Malignant Neoplasms; Maps; Mediating; Methods; Mitosis; Mitotic; Modification; Molecular; Mosaicism; Mus; Mutation; Natural regeneration; Nature; Neoplasm Metastasis; Neoplasms; Normal tissue morphology; Oncogenic; Outcome; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiologic pulse; Ploidies; Polyploid Cells; Polyploidy; Property; Regenerative Medicine; Regulation; Repression; Resistance; Skin; Stress; TP53 gene; Testing; Tissues; Transcription Coactivator; Transcription Repressor; Transcriptional Activation; Variant; base; biological adaptation to stress; cancer cell; cancer therapy; cell type; chromatin modification; daughter cell; defined contribution; design; experimental study; fly; genetic approach; in vivo; novel therapeutics; programs; promoter; radiation response; response; tool; transcription factor; tumor; tumor progression; tumorigenesis; wound healing

SUMMARY Cell division and stress response differ among tissues and are perturbed in disease. This proposal focuses on a variation called the endocycle, during which cells periodically replicate their DNA without dividing, resulting in an increase in cell size and cellular DNA content (polyploidy). This alternative growth program occurs widely in nature, including many tissues in humans (e.g. liver, heart, blood, skin). Emerging evidence indicates that cells also switch to endocycles during wound healing, regeneration, and cancer. Despite their importance, much remains unknown about how endocycles are regulated and how they contribute to tissue growth and disease. The objectives of this proposal are to define the molecular and cellular mechanisms that regulate endocycles, their modified response to DNA damage, and their contribution to genome instability and cancer. Our previous studies showed that endocycling cells in the fruit fly do not undergo programmed cell death (apoptosis) in response to radiation or other treatments that damage DNA, a property that others have shown is shared by endocycling cells in mice. The repression of cell death acts through chromatin silencing of target genes of the p53 tumor suppressor. Our previous studies also showed that both fly and human cells can be induced to switch to endocycles, and then can switch back to mitotic divisions that are extremely error prone, resulting in daughter cells with abnormal DNA content (aneuploidy). It is known that human cancer cells are frequently aneuploid and that tumors contain giant polyploid cells. Together, these observations lead to the hypothesis that a transient switch to endocycles leads to cancer cell survival with a return to mitosis causing mutations that promote cancer progression. This proposal seeks to understand the molecular mechanisms that regulate endocycles, repress apoptosis, and contribute to tumor formation and metastasis. We will use the powerful tools in the fruit fly to achieve three specific aims: 1) To determine how the repression of apoptosis is linked to the endocycle program, 2) To define the mechanism by which CycA / CDK activates the Myb-MuvB to regulate alternative cell cycle programs, 3) To determine the contribution of transient endocycles to oncogenic growth and metastasis. The outcomes of this proposal will fill a major knowledge gap in understanding the regulation of the variant endocycle growth program and its contributions to development and cancer, ultimately leading to better regenerative medicine and cancer therapies.

概括 细胞分裂和应激反应在组织之间有所不同，并且在疾病中受到干扰。该提议重点 一种称为内鼠的变体，在此期间细胞定期复制其DNA而不分裂，导致 细胞大小和细胞DNA含量（多倍体）的增加。这个替代增长计划在 大自然，包括人类中的许多组织（例如肝脏，心脏，血液，皮肤）。新兴的证据表明细胞 在伤口愈合，再生和癌症期间，还切换到内猫。尽管它们的重要性，但 对于如何调节内鼠以及它们如何对组织生长和疾病贡献，仍然不知道。 该提案的目标是定义调节内鼠的分子和细胞机制， 他们对DNA损伤的反应及其对基因组不稳定性和癌症的贡献。我们的先前 研究表明，果蝇中的内吞细胞不会在编程细胞死亡（凋亡）中 对辐射或其他损害DNA的治疗的反应，他人所显示的特性由 小鼠内吞细胞。细胞死亡的抑制通过染色质沉默的靶基因沉默 p53肿瘤抑制剂。我们先前的研究还表明，苍蝇和人类细胞都可以诱导到 切换到内环，然后可以切换回有极容易出错的有丝分裂部门，导致 具有异常DNA含量的子细胞（非整倍性）。众所周知，人类癌细胞经常 非整倍体和肿瘤含有巨大的多倍体细胞。这些观察结果一起导致了假设 瞬时转移到内猫会导致癌细胞的存活，返回有丝分裂，从而导致突变 促进癌症的进展。该提议旨在了解调节的分子机制 内吞，抑制凋亡，并导致肿瘤形成和转移。我们将使用强大的 果蝇中的工具以实现三个特定的目标：1）确定凋亡的抑制如何与 内循环程序，2）定义CYCA / CDK激活MYB-MUVB调节的机制 替代细胞周期程序，3）确定瞬时内猫对致癌生长的贡献 和转移。该提案的结果将填补理解法规的重大知识差距 内养生生长计划及其对发育和癌症的贡献，最终导致 更好的再生医学和癌症疗法。