TRANSCRIPTIONAL REPRESSION AND CELL CYCLE MECHANISMS

细胞周期停滞和退出的机制对于细胞周期至关重要 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) 生长抑制剂家族是不可分割的成员 细胞生长控制途径。虽然视网膜母细胞瘤家族的作用 G1/S 控制中的作用已得到证实，它们在完整细胞中的作用 循环退出和终末分化尚不清楚。对此 最后，我们分离出了 HBP-1，一种新的序列特异性 HMG 转录 因子，作为分化细胞中 RB 家族的特定相互作用因子。 我们的功能研究表明 HBP-1 符合关键的标准 细胞周期停滞和退出途径的参与者。首先，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- 在终末分化中受到调节，其特点是 不可逆的细胞周期退出。其次，HBP-1 作为转录因子发挥作用。 N-MYC 癌基因的阻遏物，其在器官发生和 肿瘤发生已明确。有趣的是，N-MYC 启动子是 还受到 E2F 转录因子（一种已知的 G1/S 调节因子）的调节。 综上所述，我们认为HBP-1和E2F-1构成了两个重要的 细胞周期转变的转录调节因子，这些 不同的信号可以通过 MYC 启动子整合。重点是 该提议是细胞周期控制的分子机制和 转录抑制。转录的鉴定 阻遏蛋白作为 RB 家族的靶标也是独一无二的，正如之前的大多数 E2F 等转录靶标已成为激活剂。因为HBP-l 显然可以执行这两种功能，了解细胞和 分子机制可能提供对细胞周期最好的独特见解 并退出并进入转录抑制。其机制 转录抑制尚不清楚，但可能是 作为决定基因模式的转录激活很重要 表达。细胞周期停滞和退出的机制也很关键 在肿瘤发生过程中。阐明该途径的分子机制可能 为治疗的最终发展提供基础知识 治疗侵袭性增殖肿瘤的药物，其中 与正常组织功能相关的不可逆细胞周期退出 被覆盖。

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.