p53-mediated control of numeral integrity of centrosomes

p53介导的中心体数字完整性控制

• 批准号: 7141545
• 负责人: KENJI FUKASAWA
• 金额: $ 25.38万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141545
• 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

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.

描述（由申请人提供）：染色体不稳定性（以及产生的非整倍性）已被认为是癌细胞的标志，并通过促进习惯各种恶性表型所需的遗传病变的积累来促进多步癌发生。然而，关于癌症中染色体不稳定性的原因和机制，还有很多待学。许多研究表明，在几乎所有类型的人类癌症中，中心体的异常扩增（产生了两个以上的中心体）经常发生，并且中心体扩增和非整倍性之间存在很强的关联。在有丝分裂过程中，通过形成由多个中心体（纺锤形杆）组织的异常纺锤体，导致染色体隔离误差的频率增加，在有丝分裂过程中显着特征。实际上，现在被广泛接受为癌症中染色体不稳定性的主要因素之一。中心体扩增通过几种机制发生，其中不受控制的中心体重复可能是主要原因。我们和其他人先前已经表明，p53肿瘤抑制蛋白的丧失或灭活突变导致中心体重复的失调，导致cent骨扩增的高频率，这无疑有助于与p53的损失或突变相关的整体肿瘤感应性表型。在当前赠款期间，我们集中于p53如何参与中心体重复的调节，并且我们做出了许多关键发现，以进一步了解这一重要细胞事件的分子机制。在此应用中，除了我们继续努力阐明p53本身如何调节中心体重复的分子机制以及p53的损失如何导致中心体扩增的分子机制外，我们还将将研究扩展到p53的上游分子/事件。这对于完全理解p53依赖性调节的p53依赖性调节和中心体的数字稳态是一种细胞现象，而不是“单一”的生物事件。此处提出的研究不仅将提供至关重要的信息，以充分掌握p53的肿瘤抑制活性以及p53突变在致癌中的作用，而且还导致针对中心体重复的有效癌症干预方案。这种方法可能在癌症干预中有效，因为中心体重复（如DNA合成）仅限于增殖细胞。此外，有针对性的抑制中心体重复不仅会阻止细胞分裂，还可以抑制染色体的不稳定性。