TRANSCRIPTIONAL REPRESSION AND CELL CYCLE MECHANISMS

转录抑制和细胞周期机制

• 批准号: 6018803
• 负责人: AMY S. YEE
• 金额: $ 31.16万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6018803
• 关键词: 3T3 cells; DNA binding protein; RNase protection assay; cell cycle; cell growth regulation; cell line; cytogenetics; flow cytometry; gene induction /repression; genetic promoter element; immunofluorescence technique; immunoprecipitation; microinjections; molecular biology; protein structure function; retinoblastoma protein; tissue /cell culture; transcription factor; transfection; western blottings; yeast two hybrid system

The mechanisms underlying cell cycle arrest and exit are critical to normal terminal differentiation and aberrant tumorigenesis pathways. The retinoblastoma (RB) family of growth suppressors are integral members of cell growth control pathways. While the role of the retinoblastoma family in G1/S control has been well-established, their role in complete cell cycle exit and terminal differentiation is not well-understood. To this end, we have isolated HBP-1, a new sequence specific HMG transcription factor, as a specific interactor of the RB family in differentiated cells. Our functional studies indicate that HBP-1 fit the criteria of a critical player in cell cycle arrest and exit pathways. First, the expression of HBP-1 in cells leads to efficient cell cycle arrest. HBP-1 levels are up- regulated in terminal differentiation, which is characterized by irreversible cell cycle exit. Second, HBP-1 functions as a transcriptional repressor of the N-MYC oncogene, whose role in organogenesis and tumorigenesis is well-established. Intriguingly, the N-MYC promoter is also regulated by the E2F transcription factors, a known G1/S regulator. Taken together, we propose that HBP-1 and E2F-1 constitute two important transcriptional regulators of cell cycle transitions and that these diverse signals can be integrated through the MYC promoter. The focus of this proposal are the molecular mechanisms of cell cycle control and transcriptional repression. The identification of a transcriptional repressor as an RB family target is also unique, as most previous transcriptional targets such as E2F have been activators. Because HBP-l can apparently execute both functions, understanding the cellular and molecular mechanisms may provide unique insights into both cell cycle best and exit and into transcriptional repression. The mechanisms of transcriptional repression are not well-understood, but may be as important as transcriptional activation in dictating patterns of gene expression. The mechanisms of cell cycle arrest and exit are also critical in oncogenesis. Elucidation of the molecular mechanism of this pathway may provide fundamental knowledge for the eventual development of therapeutic agents to treat aggressively proliferating tumors in which the irreversible cell cycle exit associated with normal tissue function has been overridden.

细胞周期停滞和退出的机制对于细胞周期的形成至关重要。 正常的终末分化和异常的肿瘤发生途径。的 视网膜母细胞瘤（RB）家族的生长抑制因子是视网膜母细胞瘤（RB）的组成成员。 细胞生长控制途径。虽然视网膜母细胞瘤家族 在G1/S控制中已经得到了很好的建立，它们在完整细胞中的作用 周期退出和终末分化还不清楚。本 最后，我们分离了一个新的序列特异性HMG转录因子HBP-1， 因子，作为分化细胞中RB家族的特异性相互作用物。 我们的功能研究表明，HBP-1符合一个关键的标准， 参与细胞周期阻滞和退出途径。第一，表达 细胞中的HBP-1导致有效的细胞周期停滞。HBP-1水平上升- 调节终末分化，其特征在于 不可逆细胞周期退出。第二，HBP-1作为转录因子发挥功能， N-MYC癌基因的阻遏物，其在器官发生和 肿瘤发生是公认的。有趣的是，N-MYC启动子是 也受E2 F转录因子（一种已知的G1/S调节因子）调节。 总而言之，我们认为HBP-1和E2 F-1构成了两个重要的 细胞周期转换的转录调节因子，这些 不同的信号可以通过MYC启动子整合。的焦点 这一建议是细胞周期控制的分子机制， 转录抑制一个转录本的鉴定 作为RB家族靶点的阻遏物也是独特的，因为大多数以前的 E2 F等转录靶点已成为激活因子。因为HBP-I 显然可以执行这两种功能，理解细胞和 分子机制可以提供独特的见解，既细胞周期最好的 退出并进入转录抑制。的机制 转录抑制不是很清楚，但可能是因为 转录激活在决定基因模式中同样重要 表情细胞周期停滞和退出的机制也至关重要 在肿瘤发生中。阐明这一途径的分子机制， 为最终开发治疗药物提供基础知识 用于治疗侵袭性增殖肿瘤的药物， 与正常组织功能相关不可逆细胞周期退出 被推翻了