Mitotic Checkpoint Proteins in Tumorigenesis

描述：（由申请人提供）有丝分裂检查点描述了分子 控制，监测染色体分离，一个过程，确保 将细胞的基因组忠实地传递给后代。如果这些步骤中的任何一个 失败时，有丝分裂检查点触发细胞周期停滞，以提供额外的 在细胞分裂前完成这一过程。可以说更重要的是， 肿瘤发生，但在很大程度上未被探索，是有丝分裂的第二个功能， 当没有合适的染色体发生分裂时，检查点诱导细胞死亡 种族隔离最近，有丝分裂检查点受到越来越多的关注， 因为许多癌细胞显示出染色体非整倍性，至少其中一些 可以解释为遗传显性染色体不稳定性（GIN） 表型。事实上，这种染色体的不稳定性可能在早期就起作用， 促进肿瘤抑制因子的快速丢失和获得， 原癌基因。总的来说，这些发现表明， 有丝分裂检查点和癌症途径之间的关键联系。 这是一个建议，以破译的机制背后的第二个功能， 有丝分裂检查点，即杀死经历异常染色体的细胞的检查点 种族隔离初步的数据支持了这样的假设， 异常染色体分离以依赖于信号传导的方式被杀死 从两个有丝分裂检查点蛋白BUB1和MAD3L到肿瘤抑制因子 第53页。我们想确定BUB 1和MAD3L是如何监测的， 染色体分离的连续阶段，信号故障以及两者是否 这些信号通过p53稳定作用。最后，我们将开发鼠 模型，测试有丝分裂检查点缺陷的后果， 肿瘤发生，以及开发模型，以进一步破译生物化学 检查点信号分子和p53之间的通路。我们预计 这些研究将解决一个重要的假设， 癌症，并有助于我们了解和预防这些疾病。

DESCRIPTION: (provided by applicant) The mitotic checkpoint describes molecular controls that monitor chromosome segregation, a process that ensures the faithful transfer of a cell's genome to its progeny. Should any of these steps fail, the mitotic checkpoint triggers a cell cycle arrest to provide additional time to complete the process before cell division. Arguably more important to tumorigenesis, but largely unexplored, is a second function of the mitotic checkpoint- inducing cell death when division occurs without proper chromosome segregation. Recently, the mitotic checkpoint has come under increased scrutiny because many cancer cells show chromosomal aneuploidy, at least some of which can be explained by a genetically dominant chromosome instability (GIN) phenotype. This chromosome instability may in fact be acting early in tumorigenesis to promote the rapid loss and gain of tumor suppressors and proto-oncogenes, respectively. Taken together, these findings suggest a critical link between the mitotic checkpoint and cancer pathways. This is a proposal to decipher the mechanisms underlying the second function of the mitotic checkpoint, that of killing cells which undergo abnormal chromosome segregation. Preliminary data support the hypothesis that cells showing abnormal chromosome segregation are killed in a manner dependent on signaling from two mitotic checkpoint proteins, BUB1 and MAD3L, to the tumor suppressor p53. We want to determine how BUB 1 and MAD3L, which appear to monitor successive phases of chromosome segregation, signal failures and whether both of these signals act through p53 stabilization. Finally, we will develop murine models that test the consequences of defects in the mitotic checkpoint on tumorigenesis, as well as develop models to further decipher the biochemical pathways between the checkpoint signaling molecules and p53. We anticipate that these studies will address an important hypothesis for the generation of cancers and contribute to our understanding and prevention of these diseases.