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J. Biol. Chem., Vol. 277, Issue 28, 25576-25582, July 12, 2002

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The Human Papillomavirus Oncoprotein E7 Attenuates NF-B Activation by Targeting the IB Kinase Complex^*

Dimitry Spitkovsky, Steffen P. Hehner^§, Thomas G. Hofmann^¶, Andreas Möller^§, and M. Lienhard Schmitz^**

From the  Institute for Vegetative Physiology, University of Cologne, Robert-Koch-Strasse 39, D-50931 Cologne, Germany, the ^§ German Cancer Research Center, Division of Immunochemistry (G0200), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, the ^¶ Department of General Virology, Heinrich-Pette-Institute for Experimental Virology and Immunology, Martinistrasse 52, D-20251 Hamburg, Germany, and the  University of Bern, Department for Chemistry and Biochemistry, Freiestr 3, 3012 Bern, Switzerland

Infection with high-risk human papillomaviruses (HPV) can lead to the development of cervical carcinomas. This process critically depends on the virus-encoded E6 and E7 oncoproteins, which stimulate proliferation by manipulating the function of a variety of host key regulatory proteins. Here we show that both viral proteins dose-dependently interfere with the transcriptional activity of NF-B. A variety of experimental approaches revealed that a fraction of the E7 proteins is found in association with the IB kinase complex and attenuates induced kinase activity of IB kinase  (IKK) and IKK, thus resulting in impaired IB phosphorylation and degradation. Indirect immunofluorescence shows that E7 impairs TNF-induced nuclear translocation of NF-B, thus preventing NF-B from binding to its cognate DNA. While E7 obviates IKK activation in the cytoplasm, the E6 protein reduces NF-B p65-dependent transcriptional activity within the nucleus. We suggest that HPV oncogene-mediated suppression of NF-B activity contributes to HPV escape from the immune system.

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