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

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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.