Cell cycle inhibition by CAAT Enhancer Binding Proteins (C/EBP) Hemmung des Zellzyklus durch CAAT Enhancer Binding Proteine (C/EBP)

细胞增殖和分化通常是排他性事件。一旦细胞终末分化，它们对表明分化程序占主导地位的增殖信号就变得不容易。增殖抑制和分化是如何结合在一起的，以及癌症脱钩是如何发生的，人们几乎不清楚。C/EBP蛋白在几种类型的细胞中诱导分化并同时抑制增殖。这两种功能都是通过C/EBP反式激活结构域来实现的。我们发现，来自高危型人乳头瘤病毒16型的E7癌基因将C/EBPA的抗核分裂活性与其分化功能分开。突变分析表明，E7对生长抑制和分化的分离严重依赖于E8酪蛋白激酶II磷酸化位点的完整性，而与两者、E7口袋蛋白结合能力或cdk抑制物p21无关。鉴于皮肤角质形成细胞高表达C/EBP蛋白的事实，我们的结果可能对了解乳头状瘤病毒的功能和肿瘤发生有重要意义。此外，我们还发现，细胞周期蛋白A和细胞周期蛋白E的过表达也可以使C/EBPA介导的生长停滞与分化解偶联。利用我们已经建立的分子工具，我们将研究C/EBPA如何诱导增殖停滞，以及E7如何将CEBPA介导的生长停滞从其分化功能中解脱出来。

Cell proliferation and differentiation are often exclusive events. Once cells terminally differentiate, they become refractory to proliferation signals indicating that differentiation programs are dominant. How proliferation arrest and differentiation are coupled and how in cancer decoupling occurs is barely understood. C/EBP proteins induce differentiation and concomitantly inhibit proliferation in several cell types. Both functions are mediated through the C/EBP transactivation domains. We found that the E7 oncogene from high-risk human papilloma virus type 16 separates the antimitotic activity of C/EBPa from its differentiation function. A mutation analysis showed that separation of growth arrest and differentiation by E7 was critically dependent on the integrity of the E8 casein kinase II phosphorylation site and independent of both, the E7 pocket protein binding capacity or the cdk inhibitor p21. Given the fact that skin keratinocytes highly express C/EBP proteins, our result might be important for the understanding of papilloma virus function and tumorigenesis. Furthermore, we found that overexpression of either cyclin A or cyclin E could also uncouple C/EBPa mediated growth arrest from differentiation. Using the molecular tools that we have generated, we will examine how C/EBPa induces proliferation arrest and how E7 uncouples CEBPa mediated growth arrest from its differentiation function.