Nuclear proto-oncogene products transactivate the human papillomavirus type 16 promoter.
Human papillomavirus (HPV) type 16 and 18 viral genomes are frequently detected in cervical and penile cancer biopsies. Although this strongly suggests a prominent role for HPV infection in the development of genital cancer, other genetic or environmental factors are also involved. Genital cancer is postulated to result from loss of cellular control functions, which leads to an unregulated expression of HPV oncogenic proteins. In our study, we determined the trans-activating properties of nuclear proto-oncogene proteins c-Fos, c-Jun and c-Myc on P97 enhancer/promoter activity of HPV16. Using a CAT-reporter construct containing the HPV16 enhancer/promoter element, we investigated the trans-activating effects of c-Fos, c-Jun, c-Myc, and E2 in cervical HT-3 cells. c-Fos and c-Jun overexpression resulted in a 3.3- and 3.1-fold up-regulation of CAT activity. Only 2-fold induction was determined by co-transfection with c-myc and the viral transcription factor E2. Based on these findings, we investigated the expression of HPV DNA (16 and 18) as well as nuclear proto-oncogenes (c-fos, c-jun and c-myc) in nine cervical cancers by in situ hybridisation. In six out of nine carcinomas, HPV16 and/or HPV18 DNA was detectable. All tumours showed an intense and homogeneous expression of c-fos and c-jun mRNA, while the signal for c-myc was detectable only in four specimens. These data suggest that deregulation of nuclear proto-oncogene expression may contribute to an overexpression of HPV-derived oncogenic proteins (E6 and E7), which is generally hypothesised to be an important step in the malignant transformation of HPV-associated tumours.
Nürnberg
W
W
Universitätsklinikum Rudolf Virchow, Hautklinik, Freie Universität, Berlin, Germany.
Artuc
M
M
Vorbrueggen
G
G
Kalkbrenner
F
F
Moelling
K
K
Czarnetzki
B M
BM
Schadendorf
D
D
D001483:Base Sequence; D002467:Cell Nucleus / Q000502:physiology; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016679:Genome, Viral; D006801:Humans; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology*
D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; C068651:E6 protein, Human papillomavirus type 16; C000715470:MAS1 protein, human; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C059731:oncogene protein E7, Human papillomavirus type 16