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

细胞增殖和分化往往是相互排斥的。一旦细胞最终分化，它们对增殖信号变得不耐受，这表明分化程序占主导地位。增殖抑制和分化是如何耦合的，以及在癌症中如何发生解耦，人们几乎不了解。C/EBP蛋白在多种细胞类型中诱导分化并同时抑制增殖。这两种功能都是通过C/EBP交互激活域介导的。我们发现来自高危人乳头瘤病毒16型的E7癌基因将C/EBPa的抗有丝分裂活性与其分化功能分离开来。突变分析表明，E7对生长停滞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，而不依赖于E7口袋蛋白结合能力或cdk抑制剂p21。鉴于皮肤角质形成细胞高度表达C/EBP蛋白，我们的结果可能对了解乳头状瘤病毒的功能和肿瘤发生具有重要意义。此外，我们发现cyclin A或cyclin E的过表达也可以解除C/EBPa介导的生长阻滞分化。使用我们已经生成的分子工具，我们将研究C/EBPa如何诱导增殖停滞，以及E7如何从其分化功能中解耦CEBPa介导的生长停滞。

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.