Polypoid cell cycle regulation and genome instability

摘要 细胞分裂和应激反应因组织不同而不同，在疾病中受到干扰。这项提案的重点是 一种称为内周期的变异，在此期间，细胞周期性地复制它们的DNA，而不是分裂，导致 细胞大小和细胞DNA含量的增加(多倍体)。这一替代增长计划广泛存在于 自然界，包括人类的许多组织(如肝脏、心脏、血液、皮肤)。新出现的证据表明，细胞 在伤口愈合、再生和癌症期间，也会转向内环素。尽管它们很重要，但 内环是如何调控的，它们如何促进组织生长和疾病，目前尚不清楚。 这项提议的目标是定义调节内环的分子和细胞机制， 它们对DNA损伤的修改反应，以及它们对基因组不稳定和癌症的贡献。我们以前的 研究表明，果蝇中的内周期细胞不会经历程序性细胞死亡(凋亡)。 对辐射或其他破坏DNA的治疗的反应，其他人表现出的一种特性是 小鼠体内的内周期细胞。抑制细胞死亡是通过染色质沉默靶基因起作用的。 P53肿瘤抑制因子。我们之前的研究也表明，苍蝇和人类细胞都可以被诱导成 切换到内环，然后可以切换回极易出错的有丝分裂，导致 DNA含量异常的子细胞(非整倍体)。众所周知，人类癌细胞经常是 非整倍体，肿瘤含有巨大的多倍体细胞。总而言之，这些观察结果导致了这样的假设 向内周期的短暂转换导致癌细胞存活，并恢复到有丝分裂，导致突变 促进癌症进展的物质。这一提议试图理解调控的分子机制 内周期，抑制细胞凋亡，促进肿瘤的形成和转移。我们将使用强大的 果蝇中的工具可以实现三个特定的目的：1)确定抑制细胞凋亡是如何与 内环程序，2)确定Cyca/CDK激活Myb-MuvB调节的机制 可供选择的细胞周期程序，3)确定瞬时内周期对致癌生长的贡献 和转移。这项提案的结果将填补在理解该法规方面的一个重大知识空白 变异的内周期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治疗。

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.