Mitosis, Aneuploidy and Cancer

描述（由申请人提供）：非整倍性，一种异常的染色体数目，是肿瘤细胞的共同特征，发生在85%的人类癌症中。非整倍性通常是由于有丝分裂过程中染色体分离错误引起的。肿瘤细胞中非整倍体和有丝分裂错误的高患病率促使非整倍体是肿瘤发生的一个原因的假设。然而，这一点很难确定。我们最近发现，由有丝分裂特异性运动蛋白CENP- E（着丝粒相关蛋白E）减少引起的非整倍体既促进也抑制肿瘤，这取决于环境。这些发现可能具有治疗意义，特别是因为CENP-E运动活动抑制剂目前正在临床试验中。本提案的总体目标是确定决定由CENP-E减少引起的非整倍体是否会促进或抑制肿瘤的环境依赖因素。初步研究表明，先前存在遗传不稳定水平的肿瘤容易受到非整倍体介导的肿瘤抑制，这是由于一个或多个基本染色体的两个拷贝丢失导致细胞死亡增加而发生的。Aim 1的实验将确定非整倍体介导的细胞死亡机制，并为预测哪些肿瘤易感提供依据。目的2将确定肿瘤抑制因子p53和APC （Adenomatous Polyposis Coli）减少或突变诱导的肿瘤是否易受CENP-E减少引起的非整倍体介导的细胞死亡。先前的研究表明，在缺乏p19ARF肿瘤抑制因子的动物中，减少CENP-E可以抑制肿瘤。Aim 3将扩展初步研究，确定p19ARF在有丝分裂期间染色体分离中的先前未被怀疑的作用。总之，这些实验将确定确定特定肿瘤是否易受非整倍体介导的肿瘤抑制的特征，并将为目前临床试验中使用CENP-E抑制剂提供翻译相关信息。

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.