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)

肿瘤抑制蛋白p53和c-Jun是参与许多重要细胞功能的转录因子，如DNA修复、细胞凋亡和增殖。调节这些蛋白质的稳定性对它们的细胞内功能至关重要。p53和c-Jun都以泛素依赖的方式被26S蛋白酶体降解。已知c-Jun在Ser63和73磷酸化后是稳定的。最近，我们从人红细胞中纯化了一种蛋白复合物，COP9信号体，它是26S蛋白酶体盖子复合物的同源物，并特异性磷酸化p53和c-Jun。我们确定了特定的磷酸化位点，发现c-Jun在体外被COP9信号体修饰在Ser63和73上。在即将到来的申请期内，我们将重点研究c-Jun和COP9信号体磷酸化p53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COP9信号体和26S蛋白酶体的盖子，以验证盖子对转录因子的降解至关重要，而其同源物COP9信号体则稳定这些蛋白质的假设。

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.