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DNA修复、细胞凋亡和增殖等重要细胞功能的转录因子。调节这些蛋白质的稳定性对于它们的细胞内功能是必不可少的。P53和c-Jun均被26S蛋白酶体以泛素依赖的方式降解。已知c-jun在Ser63和73上的磷酸化后稳定下来。最近，我们从人的红细胞中纯化了一个蛋白质复合体，COP9信号体，它是26S蛋白酶体LID复合体的同源物，特异性地磷酸化P53和c-Jun.我们鉴定了c-jun的磷酸化位点，发现c-jun在体外可以被COP9信号体修饰在Ser63和73上。在接下来的应用阶段，我们将重点研究COP9信号体对c-jun和p53磷酸化的生理相关性。我们将研究磷酸化对细胞内转录因子稳定性和活性的影响。我们将继续对COP9信号体和26S蛋白酶体LID进行鉴定，以检验LID对于转录因子的降解是必不可少的假设，而它的同源物COP9信号体则稳定这些蛋白质。

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.