P53 Mediated Regulation of Centrosome Duplication

P53 介导的中心体复制调节

• 批准号: 6729189
• 负责人: KENJI FUKASAWA
• 金额: $ 25.4万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729189
• 关键词: 3T3 cells; DNA replication; cell cycle; centrosome; cyclin dependent kinase; cyclins; gene deletion mutation; gene induction /repression; neoplasm /cancer genetics; neoplastic transformation; p53 gene /protein; phosphoproteins

APPLICANT'S DESCRIPTION: Chromosome instability (and resulting aneuploidy) has been recognized as a hallmark of cancer and contributes to multi-step carcinogenesis by facilitating the accumulation of genetic lesions required for the acquisition of various malignant phenotypes. However, much remains to be learned regarding the causes and mechanisms of chromosome instability in cancer. We have recently found that p53 tumor suppressor protein, the product of the most commonly mutated genes in human cancers, is involved in the control of the centrosome duplication cycle. Loss or mutational inactivation of p53 results in uncontrolled amplification of centrosomes. A deleterious consequence of centrosome hyperamplification is most prominently featured during mitosis by the formation of aberrant spindles organized by multiple centrosomes (spindle poles), leading to an increased frequency of chromosome segregation errors. Moreover, centrosome hyperamplification is commonly observed in human cancers, and that the occurrence of centrosome hyperamplification in those tumors is strongly correlated with loss or mutational inactivation of p53. This suggests that centrosome hyperamplification induced by mutation of p53 is one major factor that contributes to chromosome instability in human cancers. The goal of this research proposal is to elucidate the molecular mechanisms that control initiation of centrosome duplication, coordination of the centrosome and DNA duplication cycles, and suppression of centrosome reduplication within a single cell cycle. Elucidation of this unexplored function of p53 at a molecular level will provide vital information for fully understanding the tumor suppressor activity of p53, the role of p53 mutation in carcinogenesis, and also for designing effective cancer intervention protocols targeting p53 to block centrosome duplication. Such an approach may prove effective in cancer intervention, since centrosome duplication, like DNA replication, is restricted to proliferating cells. Moreover, blocking the centrosome duplication process results in suppression of chromosome instability as well as cell division.

申请人的描述：染色体不稳定性（以及产生的非整倍性）具有 被认为是癌症的标志，并有助于多步骤 通过促进所需的遗传病变的积累来进行致癌 采集各种恶性表型。但是，还有很多事情要 了解了染色体不稳定性的原因和机制 癌症。我们最近发现p53肿瘤抑制蛋白，该产物 在人类癌中最常见的突变基因中，参与了对照 中心体重复周期的。 p53的损失或突变失活 导致不受控制的中心体扩增。有害后果 在有丝分裂过程中，最突出的中心体高扩增是由 由多个中心体组织的异常纺锤体的形成（纺锤体 杆），导致染色体分离误差的频率增加。 此外，在人类癌症中通常观察到中心体高增加， 并且这些肿瘤中的中心体高增加的发生是 与p53的损失或突变失活密切相关。这暗示着 通过p53突变引起的中心体高增加是一个主要 导致人类癌症染色体不稳定性的因素。目标 该研究建议是阐明控制的分子机制 启动中心体重复，中心体和DNA的协调 复制周期和抑制单个中心体重复的抑制 细胞周期。在分子水平上阐明了p53的这种未开发的功能 将提供至关重要的信息，以充分了解肿瘤抑制剂 p53的活性，p53突变在致癌中的作用，也是 设计针对p53的有效癌症干预方案阻止 中心体重复。这种方法可能证明对癌症有效 干预措施，因为中心体重复（如DNA复制）受到限制 增殖细胞。此外，阻止中心体重复过程 导致抑制染色体不稳定性和细胞分裂。