The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published 21 October 2002. doi:10.1084/jem.20011053
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© Rockefeller University Press, 0022-1007/2002/10/1067 $5.00
The Journal of Experimental Medicine, Volume 196, Number 8, 1067-1078

Nucleolin as Activator of Human Papillomavirus Type 18 Oncogene Transcription in Cervical Cancer

Edgar Grinstein1, Peter Wernet1, Peter J.F. Snijders2, Frank Rösl3, Inge Weinert4, Wentao Jia4, Regine Kraft4, Christiane Schewe5, Michael Schwabe5, Steffen Hauptmann5, Manfred Dietel5, Chris J.L.M. Meijer2 and Hans-Dieter Royer1,4

1 Institut für Transplantationsdiagnostik und Zelltherapeutika, Heinrich-Heine Universität Düsseldorf, 40225 Düsseldorf, Germany
2 Department of Pathology, Vrije Universiteit Medical Center, 1007 MB Amsterdam, Netherlands
3 Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany
4 Max-Delbrück Centrum für Molekulare Medizin, 13125 Berlin, Germany
5 Institut für Pathologie, Charité, Campus Mitte, Medizinische Fakultät der Humboldt-Universität zu Berlin, 10117 Berlin, Germany

Address correspondence to Hans-Dieter Royer, Institut für Transplantationsdiagnostik und Zelltherapeutika, Heinrich-Heine Universität Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Phone: 49-211-811-6924; Fax: 49-211-811-9147; E-mail: HRoyer{at}itz.uni-duesseldorf.de

High risk human papillomaviruses (HPVs) are central to the development of cervical cancer and the deregulated expression of high risk HPV oncogenes is a critical event in this process. Here, we find that the cell protein nucleolin binds in a sequence-specific manner to the HPV18 enhancer. The DNA binding activity of nucleolin is primarily S phase specific, much like the transcription of the E6 and E7 oncoproteins of HPV18 in cervical cancer cells. Antisense inactivation of nucleolin blocks E6 and E7 oncogene transcription and selectively decreases HPV18+ cervical cancer cell growth. Furthermore, nucleolin controls the chromatin structure of the HPV18 enhancer. In contrast, HPV16 oncogene transcription and proliferation rates of HPV16+ SiHa cervical cancer cells are independent of nucleolin activity. Moreover, nucleolin expression is altered in HPV18+ precancerous and cancerous tissue from the cervix uteri. Whereas nucleolin was homogeneously distributed in the nuclei of normal epithelial cells, it showed a speckled nuclear phenotype in HPV18+ carcinomas. Thus, the host cell protein nucleolin is directly linked to HPV18-induced cervical carcinogenesis.

Key Words: tumor virus • carcinogenesis • cell cycle • proliferation • chromatin


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