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

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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.