p53-mediated control of numeral integrity of centrosomes

描述（由申请人提供）：染色体不稳定性（以及由此产生的非整倍体）已被认为是癌细胞的标志，并且通过促进获得各种恶性表型所需的遗传病变的积累，有助于多步骤癌变。然而，关于癌症中染色体不稳定的原因和机制，还有很多有待研究。大量研究表明，中心体的异常扩增（产生两个以上的中心体）在几乎所有类型的人类癌症中都经常发生，并且中心体扩增的发生与非整倍体有很强的相关性。在有丝分裂期间，中心体扩增的有害后果是由多个中心体（纺锤极）组织的异常纺锤体的形成，导致染色体分离错误的频率增加。事实上，中心体扩增现在被广泛认为是导致癌症染色体不稳定的主要因素之一。中心体扩增通过几种机制发生，其中中心体不受控制的复制可能是主要原因。我们等人之前的研究表明，p53肿瘤抑制蛋白的缺失或失活突变导致中心体复制失调，导致中心体扩增频率高，这无疑有助于与p53缺失或突变相关的整体肿瘤易感性表型。在目前的资助期间，我们专注于p53如何参与中心体复制的调节，并且我们已经取得了许多重要的发现，以进一步了解这一重要细胞事件背后的分子机制。在本次申请中，我们除了继续努力阐明p53自身如何调节中心体复制的分子机制以及p53的缺失如何导致中心体扩增外，我们还将把我们的研究扩展到p53的上游分子/事件。这对于充分理解p53对中心体复制和数量稳态的调节是一种细胞现象，而不是“单独”的生物学事件至关重要。本文提出的研究不仅将为全面掌握p53的抑瘤活性和p53突变在癌变中的作用提供重要信息，而且还将导向针对中心体复制的有效癌症干预方案。这种方法可能在癌症干预中被证明是有效的，因为中心体复制和DNA合成一样，仅限于增殖细胞。此外，靶向抑制中心体复制不仅可以阻断细胞分裂，还可以抑制染色体的不稳定性。

DESCRIPTION (provided by applicant): Chromosome instability (and resulting aneuploidy) has been recognized as a hallmark of cancer cells, and contribute to multi-step carcinogenesis by facilitating the accumulation of genetic lesions required for acquisition of various malignant phenotypes. However, much remains to be learned in respect to the causes and mechanisms of chromosome instability in cancer. A number of studies have shown that abnormal amplification of centrosomes (generation of more than two centrosomes) occurs frequently in almost all types of human cancers, and there is a strong association between occurrence of centrosome amplification and aneuploidy. The detrimental consequence of centrosome amplification is 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. Indeed, centrosome amplification is now widely accepted as one of the major factors that contribute to chromosome instability in cancer. Centrosome amplification occurs by several mechanisms, among which uncontrolled duplication of centrosomes is perhaps the leading cause. We and others have previously shown that loss or inactivating mutation of p53 tumor suppressor protein results in dysregulation of centrosome duplication, resulting in a high frequency of centrosome amplification, which undoubtedly contributes to the overall tumor suceptibility phenotype associated with loss or mutation of p53. During the current grant period, we have focused on how p53 is involved in the regulation of centrosome duplication, and we have made many critical findings for further understanding of the molecular mechanisms underlying this important cellular event. In this application, in addition to our continuing efforts to elucidate the molecular mechanism of how p53 itself regulates centrosome duplication and how loss of p53 leads to centrosome amplification, we will extend our studies to the upstream molecules/events of p53. This is critical to fully understand the p53-dependent regulation of duplication and numeral homeostasis of centrosomes as a cellular phenomenon rather than a "single-out" biological event. The studies proposed here will not only provide vital information for fully grasping the tumor suppressor activities of p53 and the role of p53 mutation in carcinogenesis, but also lead to effective cancer intervention protocols targeting centrosome duplication. Such an approach may prove effective in cancer intervention, since centrosome duplication, like DNA synthesis, is restricted to proliferating cells. Moreover, targeted inhibition of centrosome duplication will not only block cell division, but also suppress chromosome instability.