p5研究进展.ppt

Recent advances in p53 research  周建林 p53 A phosphoprotein made of 393 amino acids Got its name due to its molecular mass as it is 53 kilodalton Sequence-specific transcription factor (both an activator and a repressor) TP53 gene is located on the short arm of chromosome 17 (17p13.1) Activation of p53- upstream inputs Upstream and downstream Activated by several signals Activation of p53 - what happens? DNA-damage/stress ? 1. activation of latent p53 [latent form ? active form] enhanced DNA-binding activity enhanced transactivation activity probably also increased nuclear translocation 2. stabillization and a rapid increase in protein level? activation of response activation ? level increases 10-100x Since enhanced levels of p53 may lead to cell cycle-arrest and apoptosis, it is of critical importance that normal cells keep their p53 levels low The key to stabillization: the MDM2-p53 coupling MDM2 associates with p53’s TAD (aa 17-27) MDM2-binding leads to 1. Repression of transactivation 2. Destabillization of p53 since MDM2-binding stimulates degradation of p53 mdm2 knock-out = lethal, rescued by simultaneous deletion of p53 The key: MDM2-p53 coupling Mechanisms for stimulated degradation MDM2 = p53-specific E3 ubiquitin protein ligase MDM2 causes transport of p53 from nucleus to cytoplasma, and export is necessary for degradation MDM2 = a target gene for p53 being activated by p53 Negative feedback loop - mechanism for turning off the p53 response Induced relatively late - leaves a time window where p53 can function The outcomes of activated p53   - downstream effects Downstream response Transcriptional effects Target genes inducing cell cycle arrest Target genes inducing DNA repair Target genes promoting apoptosis Other types of effects? Cytoplasmic Roles of p53 in Apoptosis Cytoplasmically localized p53 can either directly induce Bax oligomerization or liberate proapoptotic BH3-only proteins bound to B