Regulation of cell cycle-dependent transcription via E2F and stress reponse signals Regulation der Zellzyklus-abhängigen Transkription durch E2F und Streß- Signalwege

细胞增殖受细胞外和细胞内信号传导途径的网络控制，导致细胞周期进程的启动和维持或停滞。某些细胞周期阶段之间的转换是在检查点进行调节的，这些检查点由协调调节的级联反应来监控，从而开启和关闭基因。最近的证据表明，E2 F家族的转录因子和肿瘤抑制蛋白RB不仅控制细胞周期进程所必需的基因，而且还通过激活p53（一种已知会磷酸化并控制检查点阻滞以响应DNA损伤剂的肿瘤抑制蛋白）在致癌和过度增殖信号后诱导生长阻滞和凋亡。进一步假设p53的磷酸化通过由大催化亚基和两个DNA靶向蛋白Ku 70和Ku 80组成的DNA依赖性激酶（DNA-PK）发生。DNA-PK还参与DNA双链断裂修复和免疫球蛋白基因的重组。基于我们最近的研究发现，E2 F-因子通过一个保守的结构域与Ku 70物理相互作用，并可以被DNA-PK全酶磷酸化，该研究项目提出，E2 F和DNA-PK的功能相互作用废除E2 F依赖的转录，从而聚集由DNA损伤剂诱导的抗增殖和凋亡信号。

Cell proliferation is controlled by a network of extracellular and intracellular signalling pathways leading either to initiation and maintenance, or arrest of cell cycle progression. Transitions between certain cell cycle stages are regulated at checkpoints monitored by coordinately regulated cascades turning genes on and off. Recent evidence suggests that transcription factors of the E2F-family and the tumor suppressor protein RB do not only control genes necessary for cell cycle progression, but also induce growth arrest and apoptosis upon oncogenic and hyperproliferative signals by activating p53, a tumor suppressor protein known to become phosphorylated and govern checkpoint arrest in response to DNA damaging agents. It is further supposed that phosphorylation of p53 occurs through a DNA-dependent kinase (DNA-PK) composed of a large catalytic subunit and two DNA-targeting proteins, Ku70 and Ku 80. DNA-PK is also involved in DNA double-strand break repair and recombination of immunoglobin genes. Based on our recent findings that E2F-factors physically interact via a conserved domain with Ku70 and can be phosphorylated by the DNA-PK holoenzyme, the research project proposes that funtional interaction of E2F and DNA-PK abrogates E2F-dependent transcription and thereby congregate the antiproliferative and apoptotic signals induced by DNA damaging agents.