Control of interferon signaling in human papillomavirus infection.
Human papillomaviruses (HPV) infect mucosal and cutaneous epithelium resulting in several types of pathologies, most notably, cervical cancer. Persistent infection with sexually transmitted oncogenic HPV types represents the major risk factor for the development of cervical cancer. The development of HPV-associated cervical cancer has been closely linked to the expression of the viral oncogenes E6 and E7 in the tumor cells. The major viral oncoproteins, E6 and E7, target the cellular tumor suppressor gene products p53 and Rb, respectively. As detailed within, these interactions result in the stimulation of proliferation and the inhibition of apoptosis, thus representing major oncogenic insults to the infected cell. In addition to mediating transformation, the E6 and E7 genes also play significant roles in altering the immune response against infected cells by suppressing interferon (IFN) expression and signaling. At the clinical level, IFNs have been used in the treatment of HPV-associated cervical intraepithelial neoplasia (CIN) or cervical cancers with mixed results. The success of the treatment is largely dependent on the subtype of HPV and the immune response of the patients. Despite this inefficiency, the increasing knowledge about the regulation of IFN signaling pathways at molecular level may hold a promise for the use of new therapeutic strategies against HPV infection. Studies on the regulation of the function of IFN-inducible gene products by the E6 and E7 may lead to the development of new therapeutic approaches based on strategies that modify the function of the HPV oncoproteins and restore IFN-signaling pathways through endogenous control mechanisms.
Koromilas
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Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste.-Catherine Road, Montréal, Québec, Canada H3T 1E2. akoromil@ldi.jgh.mcgill.ca
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Matlashewski
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D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D007372:Interferons / Q000276:immunology* / Q000502:physiology* / Q000627:therapeutic use; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017471:Receptors, Interferon / Q000378:metabolism; D015398:Signal Transduction; D014412:Tumor Virus Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D009856:Oncogene Proteins, Viral; D017471:Receptors, Interferon; D007372:Interferons