Spindle Assembly Checkpoint, Chromosome Stability, and Cancer

点击翻译按钮获取中文摘要

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.