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: 7253398
• 负责人: KENJI FUKASAWA
• 金额: $ 24.64万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253398
• 关键词: 3-aminobenzamide; Abbreviations; Adult; Affinity; Aneuploidy; Aphidicolin; Appendix; Binding; Biological; Bromodeoxyuridine; CCL18 gene; Cancer Intervention; Cell Cycle Arrest; Cell division; Cells; Centrosome; Chromosomal Instability; Chromosome Segregation; Chromosome abnormality; DAPI; DNA biosynthesis; DNA chemical synthesis; Embryo; Ensure; Epithelial Cells; Event; Fibroblasts; Foundations; Frequencies; Funding; Generations; Genetic; Genomics; Glutathione S-Transferase; Goals; Grant; Green Fluorescent Proteins; Heat shock proteins; Heat-Shock Proteins 70; Homeostasis; Human; Image; In Vitro; Interphase Cell; Lead; Learning; Left; Lesion; Link; Localized; Maintenance; Malignant Neoplasms; Mediating; Mitosis; Molecular; Mus; Mutation; Numbers; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Play; Poly(ADP-ribose) Polymerases; Post-Translational Protein Processing; Predisposition; Proliferating; Protein Family; Protein p53; Proteins; Protocols documentation; Regulation; Research; Research Personnel; Research Proposals; Role; Skin; TP53 gene; Testing; Text; Transactivation; Transcriptional Activation; Tumor Suppressor Proteins; Up-Regulation; Uridine; anaphase-promoting complex; base; cancer cell; carcinogenesis; comparative; grasp; hydroxyurea; in vivo; malignant phenotype; member; mortalin; poly ADP-ribose glycohydrolase; programs; red fluorescent protein; tumor; tumor progression

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（以及由此产生的非整倍性）已被认为是癌细胞的标志，并通过促进获得各种恶性表型所需的遗传病变的积累而促成多步致癌。然而，关于癌症中染色体不稳定性的原因和机制仍有许多需要了解的地方。大量研究表明，中心体异常扩增（产生两个以上的中心体）在几乎所有类型的人类癌症中频繁发生，并且中心体扩增的发生与非整倍体之间存在很强的关联。中心体扩增的有害后果在有丝分裂期间通过由多个中心体（纺锤体极）组织的异常纺锤体的形成而突出，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中染色体不稳定的主要因素之一。中心体扩增的发生有多种机制，其中中心体的不受控制的复制可能是主要原因。我们和其他人先前已经表明，p53肿瘤抑制蛋白的缺失或失活突变导致中心体复制失调，导致中心体扩增的高频率，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，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。在本申请中，除了我们继续努力阐明p53本身如何调节中心体复制以及p53丢失如何导致中心体扩增的分子机制外，我们还将研究扩展到p53的上游分子/事件。这是至关重要的，以充分了解p53依赖的调节复制和数量的中心体作为一种细胞现象，而不是一个“单挑”的生物事件的稳态。这些研究不仅为全面掌握p53的抑癌活性和p53突变在肿瘤发生中的作用提供了重要信息，而且还将导致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，如DNA合成，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，还可以抑制染色体不稳定性。