P16 AND CELL SENESCENCE AND ONCOGENESIS

P16 与细胞衰老和癌发生

• 批准号: 6137470
• 负责人: MANUEL ORESTES DIAZ
• 金额: $ 31.73万
• 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/6137470
• 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、CDKN2) 编码 p16，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常见的事件 致癌过程。 P16 在大多数正常人体内的表达水平非常低 细胞，包括淋巴细胞及其前体细胞，但上调 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，并且 INK4A 的缺失或失活会导致衰老的进展 衰老时生长停滞的肿瘤性克隆。 失活 INK4A通过基因缺失、点突变和DNA甲基化已被 在肿瘤细胞中已有报道。 根据申请人之前的情况 结果，他假设在一些肿瘤细胞中 p16 受到抑制 表达也可以通过转录后下调来实现。 该项目的具体目标是： 1）研究p16在 通过转染后 p16 的表达促进衰老和肿瘤发生 表达载体，以及通过反义下调其表达 策略。 2）研究正常情况下p16的调控机制 衰老细胞和肿瘤细胞。 3）转录后研究 白血病和淋巴瘤细胞系中 p16 的下调。 4) 测量 原发性中 INK4A 转录后下调的发生率 白血病和淋巴瘤。 在肿瘤发生过程中，细胞永生化是 实现完全恶性转化的重要一步。 P16参加 在细胞衰老的控制中。 因此，了解这一点很重要 它在衰老和永生细胞中的作用和转录调控。 由于在某些淋巴瘤和 ALL 细胞系中，INK4A 表达在 转录后水平，重要的是确定这种现象是否 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 机制探索操纵它进行治疗的可能性 目的。