Mitosis, Aneuploidy and Cancer

描述（由申请人提供）：非整倍性，一种染色体数目异常，是肿瘤细胞的常见特征，发生在约85%的人类癌症中。非整倍体常由于有丝分裂时染色体分离错误而产生。肿瘤细胞中非整倍体和有丝分裂错误的高发生率提示了非整倍体是肿瘤发生的原因的假设。然而，这一点很难确定。我们最近发现，有丝分裂特异性驱动蛋白样运动蛋白CENP- E（着丝粒相关蛋白-E）的减少引起的非整倍体既促进又抑制肿瘤，这取决于上下文。这些发现可能具有治疗意义，特别是因为CENP-E运动活性抑制剂目前正在临床试验中。该提案的总体目标是定义决定CENP-E减少引起的非整倍性是否会促进或抑制肿瘤的上下文相关因素。初步研究表明，具有预先存在的遗传不稳定性水平的肿瘤易受非整倍性介导的肿瘤抑制的影响，这是由于一个或多个必需染色体的两个拷贝丢失引起的细胞死亡增加而发生的。目的1中的实验将确定非整倍体介导的细胞死亡的机制，并提供预测哪些肿瘤易感的基础。目的2将确定由肿瘤抑制因子p53和APC（Adenomatous Polyposis Coli）的减少或突变诱导的肿瘤是否对由CENP-E减少引起的非整倍体介导的细胞死亡敏感。先前的研究表明，CENP-E的减少抑制了缺乏p19 ARF肿瘤抑制因子的动物的肿瘤。目的3将扩大初步研究，确定了一个以前未被怀疑的作用p19 ARF在有丝分裂过程中的染色体分离。总之，这些实验将定义确定给定肿瘤是否对非整倍体介导的肿瘤抑制敏感的特征，并将为目前在临床试验中使用CENP-E抑制剂提供诊断相关信息。 公共卫生相关性：癌症是美国第二大最常见的死亡原因。细胞分裂过程中的错误在癌细胞中很常见，但这些错误对肿瘤的影响是复杂的。该提案中的实验将确定细胞分裂过程中的错误如何影响肿瘤，最终目标是产生临床有用的疗法。

DESCRIPTION (provided by applicant): Aneuploidy, an abnormal chromosome number, is a common characteristic of tumor cells, occurring in ~85% of all human cancers. Aneuploidy frequently arises due to errors in chromosome segregation during mitosis. The high prevalence of aneuploidy and mitotic errors in tumor cells prompted the hypothesis that aneuploidy is a cause of tumor genesis. However, this has been difficult to establish. We recently discovered that aneuploidy caused by reduction of the mitosis-specific kinesin-like motor protein CENP- E (CENtromere associated Protein-E) both promotes and suppresses tumors, depending on the context. These findings may have therapeutic implications, particularly since an inhibitor of CENP-E motor activity is currently in clinical trials. The overall goal of this proposal is to define the context-dependent factors that determine whether aneuploidy caused by reduction of CENP-E will promote or suppress tumors. Preliminary studies suggest that tumors with a pre-existing level of genetic instability are susceptible to aneuploidy-mediated tumor suppression, which occurs due to an increase in cell death caused by loss of both copies of one or more essential chromosomes. Experiments in Aim 1 will determine the mechanism(s) of aneuploidy-mediated cell death, and provide a basis to predict which tumors are susceptible. Aim 2 will determine whether tumors induced by reduction or mutation of the tumor suppressors p53 and APC (Adenomatous Polyposis Coli) are susceptible to aneuploidy-mediated cell death caused by reduction of CENP-E. Previous studies have shown that reduction of CENP-E suppresses tumors in animals lacking the p19ARF tumor suppressor. Aim 3 will extend preliminary studies that identified a previously unsuspected role for p19ARF in chromosome segregation during mitosis. Together, these experiments will define the characteristics that determine whether a given tumor is susceptible to aneuploidy-mediated tumor suppression and will provide translationally relevant information for use of the CENP-E inhibitor currently in clinical trials. PUBLIC HEALTH RELEVANCE: Cancer is the second most common cause of death in the USA. Errors during cell division are common in cancer cells, but the effects of these errors on tumors are complex. The experiments in this proposal will define how errors during cell division affect tumors, with the ultimate goal of producing clinically useful therapies.