P53 Mediated Regulation of Centrosome Duplication

申请者描述：染色体不稳定(以及由此产生的非整倍体) 被认为是癌症的标志，并有助于多步骤 通过促进基因损伤的积累而致癌 各种恶性表型的获得。然而，还有很多事情要做。 了解到染色体不稳定的原因和机制 癌症。我们最近发现P53抑癌蛋白的产物 人类癌症中最常见的突变基因中的一种，参与了控制 中心体复制周期。P53基因缺失或突变失活 导致中心体的不受控制的放大。有害的后果 中心体过度放大是有丝分裂过程中最显著的特征，通过 由多个中心体(纺锤体)组织的异常纺锤体的形成 两极)，导致染色体分离错误的频率增加。 此外，中心体过度放大在人类癌症中也很常见， 而中心体过度放大在这些肿瘤中的发生是 与P53的缺失或突变失活密切相关。这表明 由P53突变引起的中心体过度扩增是主要的 导致人类癌症中染色体不稳定的因素。的目标是 这项研究计划旨在阐明控制的分子机制。 中心体复制的启动、中心体与DNA的协调 复制周期，并抑制单个 细胞周期。从分子水平阐明P53的这一未知功能 将为全面了解肿瘤抑制因子提供重要信息 P53的活性，P53突变在癌变中的作用，以及 设计有效的针对p53的癌症干预方案以阻断 中心体复制。这种方法可能会被证明对癌症有效。 干预，因为中心体复制，如DNA复制，是有限的 到增殖的细胞。此外，阻止中心体复制过程 导致抑制染色体不稳定性和细胞分裂。

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.