P16 AND CELL SENESCENCE AND ONCOGENESIS

P16 与细胞衰老和癌发生

• 批准号: 2856290
• 负责人: MANUEL ORESTES DIAZ
• 金额: $ 30.8万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-15 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856290
• 关键词: antisense nucleic acid; carcinogenesis; cell senescence; cyclin dependent kinase; enzyme activity; enzyme inhibitors; gene induction /repression; human genetic material tag; human tissue; immunocytochemistry; leukemia; lymphoma; neoplasm /cancer genetics; polymerase chain reaction; posttranscriptional RNA processing; tissue /cell culture; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION: (Applicant's Abstract) The tumor suppressor gene INK4A (MTS1, CDK41, CDKN2) codes for p16, an inhibitor of the G1 cyclin-dependent kinases CDK4 and CDK6. Deletion or inactivation of this gene is a frequent event in the oncogenic process. P16 is expressed at very low levels in most normal cells, including lymphoid cells and their precursors, but it is up-regulated by unknown mechanisms before senescence. The applicant proposes that p16 up-regulation partially mediates the irreversible cell cycle arrest of senescence, and that deletion or inactivation of INK4A allows progression of a neoplastic clone that has growth arrested at senescence. Inactivation of INK4A by gene deletion, point mutation, and DNA methylation has been reported in neoplastic cells. On the basis of the applicant's previous results, he postulates that in some neoplastic cells suppression of p16 expression can also be achieved by post-transcriptional down-regulation. The specific aims of this project are: 1) To study the role of p16 in senescence and oncogenesis through expression of p16 from transfected expression vectors, and down-regulation of its expression by antisense strategies. 2) To study the mechanisms of p16 regulation in normal senescent cells and neoplastic cells. 3) To study the post-transcriptional down-regulation of p16 in leukemia and lymphoma cell lines. 4) To measure the prevalence of post-transcriptional down-regulation of INK4A in primary leukemias and lymphomas. During oncogenesis, cell immortalization is an essential step to achieve full malignant transformation. P16 participates in the control of cell senescence. Therefore, it is important to understand its role and transcriptional regulation in senescent and immortal cells. Since in some lymphoma and ALL cell lines INK4A expression is inhibited at a post-transcriptional level, it is important to determine if this phenomenon is relevant to oncogenesis in primary tumors. If the post-transcriptional down-regulation of p16 is relevant, we should try to understand its mechanism to explore the possibility of manipulating it for therapeutic purposes.

描述：（申请人的摘要）肿瘤抑制基因INK4A（MTS1， CDK41，CDKN 2）编码p16，一种G1细胞周期蛋白依赖性激酶抑制剂 CDK4和CDK6。 该基因的缺失或失活是一个常见的事件， 致癌过程 P16在大多数正常人中以非常低的水平表达。 细胞，包括淋巴细胞及其前体，但它是上调 在衰老之前通过未知的机制。 申请人建议，P16 上调部分介导不可逆的细胞周期停滞， 衰老，而INK4A的缺失或失活允许衰老的进展。 在衰老时生长停滞的肿瘤克隆。 失活 INK4A通过基因缺失、点突变和DNA甲基化而被发现， 在肿瘤细胞中报告。 根据申请人以前的 结果，他假设在某些肿瘤细胞中，p16的抑制 表达也可以通过转录后下调来实现。 本课题的具体目标是：1）研究p16在人肝癌细胞中的作用， 衰老和肿瘤发生通过表达p16从转染 表达载体，并通过反义核酸下调其表达 战略布局 2)目的：探讨p16基因在正常人肝组织中的调控机制。 衰老细胞和肿瘤细胞。 3)为了研究转录后的 白血病和淋巴瘤细胞系中p16的下调。 4)测量 原发性肝癌中INK4A转录后下调的普遍性 白血病和淋巴瘤。 在肿瘤发生过程中，细胞永生化是一种 是实现全面恶性转化的关键步骤。 P16参与 在控制细胞衰老中的作用。 因此，重要的是要了解 其在衰老和永生细胞中作用和转录调控。 由于在一些淋巴瘤和ALL细胞系中，INK4A表达被抑制， 在转录后水平，重要的是要确定这种现象， 与原发性肿瘤的发生有关。 如果转录后 p16的下调是相关的，我们应该尝试了解它的 机制，探讨操纵它的治疗的可能性， 目的