The E6/E7-genes of cancer associated human papilloma viruses as targets of tumor supression

Conversion of HPV 18 positive non-tumorigenic HeLa-fibroblast hybrids to invasive growth involves loss of TNF-α mediated repression of viral transcription and modification of the AP-1 transcription complex

“…Moreover, as previously shown, viral gene expression becomes selectively suppressed when nonmalignant cells were injected in nude mice (Bosch et al, 1990). It is assumed that transcriptional downregulation is mainly mediated by macrophages and macrophage-derived cytokines (zur Hausen, 1994).…”

“…Dierences in the transcriptional regulation of the very same HPV 18 transcription cassette embedded in cells diering only in their chromosomal complement (RoÈ sl et al, 1988) became not only evident by the transcriptional suppression of HPV 18 E6/E7 mRNA exclusively in non-tumorigenic hybrids after heterotransplantation into immunocompromised animals (Bosch et al, 1990), but also by their diering sensitivity against macrophage-derived cytokines (RoÈ sl et al, 1994;Kleine et al, 1995;see also Figures 1 and 9, respectively). To investigate whether these dierences can be correlated either with already pre-existing or TNF-a induced alterations in AP-1 composition, Western blots and electrophoretic-mobility shift assays (EMSA) were performed (see Figures 2 and 3).…”

“…Since non-tumorigenic hybrids, their tumorigenic segregants and HeLa cells share comparable growth properties in tissue culture (Stanbridge, 1984), it was proposed that viral suppression in non-malignant cells upon inoculation in nude mice (Bosch et al, 1990) is mediated by the attraction of cytokine-releasing macrophages, which became activated by the expression of chemokines such as the`monocyte-chemoattractant-protein-1' gene (MCP-1) (Rollins et al, 1989). As previously shown for`CGL3'-and HeLa cells (RoÈ sl et al, 1994, see also Figure 9), concomitant with the inability to down-regulate HPV 18 transcription, TNF-a was also not further able to induce MCP-1 expression in the tumorigenic c-fos converted clones (Figure 9).…”

“…For this reason, the working hypothesis has been put forward suggesting that the viral upstream regulatory region (URR) might be a direct target for an intracellular regulatory pathway, which negatively interferes with viral transcription at the level of E6/E7 mRNA initiation (zur Hausen, 1994;zur Hausen and RoÈ sl, 1994). This cannot only be deduced from RNA/ RNA in-situ hybridization studies on primary tissue sections, but also from somatic cell hybridization experiments (Stanbridge, 1984) demonstrating a differential regulation of E6/E7 gene expression in tumorigenic and non-tumorigenic cells (RoÈ sl et al, 1988;Bosch et al, 1990; Bartsch et al, 1992; Khan et al, 1993). Monitoring cytokine sensitivity for instance, TNF-a treatment results in a selective down-regulation of HPV 18 transcription exclusively in non-malignant HeLa-®broblast hybrids, while viral gene expression in tumorigenic segregants obtained from the very same hybrids or in parental HeLa cells was not aected under the same experimental conditions (RoÈ sl et al, 1994).…”

The Viral Etiology of AIDS‐Associated Malignancies

“…Anogenital tract HPVs, of which ~40 have been identified, are divided into those which confer a "low risk" (types 6, 11, 42) or a "high risk" (types 16, 18, 31) for cervical cancer Sakai et al, 1996;zur Hausen, 1999zur Hausen, , 2000. Studies performed by Harold Zur Hausen's laboratory provided the first definitive evidence that HPVs were present in genital cancers (Bosch et al, 1991;Durst et al, 1983;Gissmann et al, 1984;Schwarz et al, 1985;zur Hausen, 1999zur Hausen, , 2000zur Hausen et al, 1975zur Hausen et al, , 1981. After more than 20 years of work, HPVs are now recognized as a necessary cause in 95% of invasive cervical cancers worldwide (Walboomers et al, 1999).…”