Spindle Assembly Checkpoint, Chromosome Stability, and Cancer

描述（由申请人提供）：非整倍体是癌症的一个突出表型。它指的是由于整个染色体的丢失或获得而导致的细胞中正常染色体数量的偏差。在大多数情况下，非整倍体是由有丝分裂错误引起的。与DNA损伤不同，一旦细胞变成非整倍体，几乎没有办法纠正丢失或获得的染色体。该细胞及其后代将保持非整倍体，如果细胞在随后的有丝分裂中再次失去或获得染色体，则非整倍体可能会恶化。由于非整倍性大规模地改变了基因组，人们一定会问：细胞会对此产生反应吗？我们之前的研究表明，非整倍体可以激活p53并导致凋亡细胞死亡。我们发现p53的激活依赖于ATM激酶，而ATM激酶是由非整倍体细胞中活性氧（ROS）水平升高激活的。这些结果表明非整倍体检查点的存在限制了非整倍体细胞的转化潜力。有趣的是，非整倍体似乎优先激活p53介导的细胞凋亡，而不是衰老。另一方面，当p53失活时，非整倍体诱导强烈的衰老和p16表达。因此，当p53通路失效时，非整倍体检查点通过诱导p53介导的细胞死亡和衰老来阻止非整倍体细胞的增殖。我们的具体目标是：1)阐明非整倍体如何激活p53介导的细胞凋亡；2)确定p53缺失时非整倍体如何诱导衰老；3)证明衰老程序的诱导在防止非整倍体诱导的肿瘤发生中起作用。

DESCRIPTION (provided by applicant): Aneuploidy is a prominent phenotype of cancer. It refers to deviations from the normal number of chromosomes in a cell, as a result of whole-chromosome loss or gain. In most cases, aneuploidy is caused by mitotic errors. Unlike DNA damage, once a cell becomes aneuploid, there is almost no way to correct the lost or the gained chromosomes. This cell and its descendants will remain aneuploid and the aneuploidy may worsen if the cell loses or gains chromosomes again in subsequent mitoses. As aneuploidy alters the genome in a large scale, one must ask: do cells mount a response to it? Our previous work demonstrated that aneuploidy could activate p53 and cause apoptotic cell death. We showed that the activation of p53 depended on the ATM kinase which was activated by the elevated levels of reactive oxygen species (ROS) in aneuploid cells. These results suggest the existence of an aneuploidy checkpoint that limits the transformation potential of an aneuploid cell. Intriguingly, aneuploidy seems to preferentially activate p53-mediated apoptosis, instead of senescence. On the other hand, when p53 is inactivated, aneuploidy induces robust senescence and p16 expression. Thus, the aneuploidy checkpoint prevents the proliferation of aneuploid cells by induce p53- mediated cell death and senescence when the p53 pathway fails. Our specific aims are: 1) to elucidate how aneuploidy activates p53-mediated apoptosis; 2) to determine how aneuploidy induces senescence in the absence of p53; and 3) to demonstrate that the induction of the senescence program plays a role in preventing aneuploidy-induced tumorigenesis. PUBLIC HEALTH RELEVANCE: We will carry out experiments designed to understand how aneuploidy checkpoint operates to prevent tumorigenesis. The goals of this grant are to elucidate the mechanisms that cause p53-mediated apoptosis and p16-dependent senescence in aneuploid cells.