TRANSCRIPTIONAL REPRESSION AND CELL CYCLE MECHANISMS

细胞周期停滞和退出的机制对 正常的终末分化和异常的肿瘤发生途径。这个 视网膜母细胞瘤(RB)家族是生长抑制因子家族的重要成员 细胞生长控制途径。而视网膜母细胞瘤家族的作用 在G1/S调控中已经确立，它们在完整细胞中的作用 周期退出和末端分化还没有被很好地理解。对这件事 最后，我们克隆了一种新的序列特异性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因子。 我们的功能研究表明，HBP-1符合临界 细胞周期停滞和退出途径的参与者。第一，表达 细胞内的HBP-1导致有效的细胞周期停滞。HBP-1水平上升- 在末端分化中调节的，其特征是 不可逆转的细胞周期退出。第二，HBP-1作为转录因子发挥作用 N-myc癌基因的抑制子，其在器官发生和 肿瘤发生学是公认的。耐人寻味的是，N-myc启动子 也受到E2F转录因子的调节，这是一种已知的G1/S调节因子。 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。的关注点 这一建议是细胞周期控制的分子机制和 转录抑制。一种转录本的鉴定 抑制子作为RB家族的靶标也是独一无二的，就像以前大多数 转录靶标，如E2F，一直是激活剂。因为高血压-L 显然可以执行这两种功能，理解细胞和 分子机制可能为这两种细胞周期提供独特的见解 然后退出并进入转录抑制。它的作用机制 转录抑制并没有被很好地理解，但可能是 转录激活在决定基因模式中的重要作用 表情。细胞周期停滞和退出的机制也是至关重要的 在肿瘤形成方面。阐明这一途径的分子机制可能 为治疗学的最终发展提供基础知识 治疗侵袭性增殖性肿瘤的药物 与正常组织功能相关的不可逆细胞周期退出 已被覆盖。

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.