Spindle Assembly Checkpoint, Chromosome Stability, and Cancer

描述(申请人提供)：非整倍体是一种突出的癌症表型。它指的是细胞中由于整个染色体的丢失或获得而偏离正常染色体数量的情况。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。这个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，非整倍体可能会恶化。随着非整倍体大规模改变基因组，人们必须问：细胞对此有反应吗？我们以前的工作证明，非整倍体可以激活P53，导致细胞凋亡。我们发现，P53的激活依赖于非整倍体细胞中活性氧物种(ROS)水平升高而激活的ATM激酶。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的表达。因此，当P53途径失效时，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)确定在没有P53的情况下，非整倍体如何诱导衰老；以及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发挥作用。 公共卫生相关性：我们将进行实验，旨在了解非整倍体检查点是如何运作的，以防止肿瘤发生。这项资助的目的是阐明在非整倍体细胞中导致p53介导的细胞凋亡和p16依赖的衰老的机制。

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.