Die Rolle des COP9 Signalosoms bei der Regulation der Ubiquitin- und Proteasom-abhängigen Proteolyse von p53, c-Jun und p27 (The role of the COP9 signalosome in the regulation of the ubiquitin- and proteasome-dependent proteolysis of p53,c-Jun and p27)

COP9 信号体在 p53、c-Jun 和 p27 泛素和蛋白酶体依赖性蛋白水解调节中的作用

• 批准号: 5109336
• 负责人: Professor Dr. Wolfgang Dubiel
• 金额: --
• 依托单位: Institut für Experimentelle Innere Medizin
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 1998
• 资助国家: 德国
• 起止时间: 1997-12-31 至 2003-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5109336?language=en
• 关键词: Die; Rolle; des; COP9; Signalosoms

The tumor suppressor protein p53 and c-Jun are transcription factors involved in a number of important cellular functions such as DNA repair, apoptosis and proliferation. The regulation of the stability of these proteins is essential for their intracellular functions. Both p53 and c-Jun are degraded by the 26S proteasome in an ubiquitin-dependent manner. c-Jun is known to be stabilized upon phosphorylation on Ser63 and 73. Recently we purified a protein complex, COP9 signalosome, from human red blood cells which is a homolog of the 26S proteasome lid complex and specifically phosphorylates p53 and c-Jun. We identified the specific phosphorylation sites and found that c-Jun is modified on Ser63 and 73 by COP9 signalosome in vitro. In the forthcoming application period we will focus on the physiological relevance of c-Jun and p53 phosphorylation by COP9 signalosome. We will study the impact of phosphorylation on stability and activity of the transcription factors in cells. We will continue to characterize COP9 signalosome and 26S proteasome lid to test the hypothesis that the lid is essential for degradation of transcription factors whereas its homolog, COP9 signalosome, stabilizes these proteins.

肿瘤抑制蛋白p53和c-Jun是参与许多重要细胞功能如DNA修复、凋亡和增殖的转录因子。调节这些蛋白质的稳定性对其细胞内功能至关重要。p53和c-Jun都以泛素依赖的方式被26 S蛋白酶体降解。已知c-Jun在Ser 63和73上磷酸化后稳定。最近，我们从人红细胞中分离纯化了一种26 S蛋白酶体复合物COP 9信号体，它是26 S蛋白酶体复合物的同源物，能特异性磷酸化p53和c-Jun，并鉴定了其特异性磷酸化位点，发现c-Jun在体外被COP 9信号体修饰在Ser 63和Ser 73上。在即将到来的应用阶段，我们将专注于c-Jun和p53磷酸化的COP 9信号体的生理相关性。我们将研究磷酸化对细胞中转录因子的稳定性和活性的影响。我们将继续表征COP 9信号体和26 S蛋白酶体盖子，以检验盖子对于转录因子的降解是必不可少的，而其同系物COP 9信号体稳定这些蛋白质的假设。