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Journal of Virology, May 2001, p. 4283-4296, Vol. 75, No. 9
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.9.4283-4296.2001

Papillomavirus Type 16 Oncogenes Downregulate Expression of Interferon-Responsive Genes and Upregulate Proliferation-Associated and NF-kappa B-Responsive Genes in Cervical Keratinocytes

Matthias Nees,1,dagger Joel M. Geoghegan,1 Tehila Hyman,1 Stephan Frank,2 Lance Miller,3 and Craig D. Woodworth1,*

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute,1 and National Institute of Neurological Disorders and Stroke,2 Bethesda, and NCI Array Facility, Advanced Technology Center, Gaithersburg,3 Maryland

Received 13 October 2000/Accepted 1 February 2001

Infection with high-risk human papillomaviruses (HPV) is a major risk factor for development of cervical cancer. Expression of the HPV E6 and E7 oncoproteins increases in differentiating keratinocytes, resulting in inactivation of the p53 and retinoblastoma proteins, two important transcriptional regulators. We used cDNA microarrays to examine global alterations in gene expression in differentiating cervical keratinocytes after infection with retroviruses encoding HPV type 16 (HPV-16) E6 and E7. Expression of 80 cellular genes (approximately 4% of the genes on the array) was altered reproducibly by E6 and/or E7. Cluster analysis classified these genes into three functional groups: (i) interferon (IFN)-responsive genes, (ii) genes stimulated by NF-kappa B, and (iii) genes regulated in cell cycle progression and DNA synthesis. HPV-16 E6 or a dominant negative p53 protein downregulated multiple IFN-responsive genes. E6 decreased expression of IFN-alpha and -beta , downregulated nuclear STAT-1 protein, and decreased binding of STAT-1 to the IFN-stimulated response element. E7 alone was less effective; however, coexpression of E6 and E7 downregulated IFN-responsive genes more efficiently than E6. The HPV-16 E6 protein also stimulated expression of multiple genes known to be inducible by NF-kappa B and AP-1. E6 enhanced expression of functional components of the NF-kappa B signal pathway, including p50, NIK, and TRAF-interacting protein, and increased binding to NF-kappa B and AP-1 DNA consensus binding sites. Secretion of interleukin-8, RANTES, macrophage inflammatory protein 1alpha , and 10-kappa Da IFN-gamma -inducible protein were increased in differentiating keratinocytes by E6. Thus, high-level expression of the HPV-16 E6 protein in differentiating keratinocytes directly alters expression of genes that influence host resistance to infection and immune function.

* Corresponding author. Present address: Biology Department, Clarkson University, Potsdam, NY 13699-5805. Phone: (315) 268-2391. Fax: (315) 268-7118. E-mail: woodworth{at}clarkson.edu.

dagger Present address: Department of Surgery, Division of Molecular Diagnostics and Therapy, University of Heidelberg, 69120 Heidelberg, Germany.

Journal of Virology, May 2001, p. 4283-4296, Vol. 75, No. 9
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.9.4283-4296.2001


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