Alternatively spliced HPV-18 E6* protein inhibits E6 mediated degradation of p53 and suppresses transformed cell growth.
The E6 proteins originating from the tumour-associated Human Papillomavirus (HPV) types 16 and 18 have been shown to bind to and target the tumour suppressor protein, p53, for ubiquitin-mediated degradation. However, in cell lines derived from cervical neoplasias, the predominant early region transcripts are spliced and encode truncated forms of E6, termed E6*. We report here that HPV-18 E6* protein will interact both with the full-length E6 proteins from HPV-16 and HPV-18 and also with E6-AP, and subsequently blocks the association of full length E6 protein with p53. We also show that, as a result of this block, E6* can inhibit E6-mediated degradation of p53 both in vitro and in vivo. The biological consequences of this are increased transcriptional activity on p53-responsive promoters and an inhibition of cell growth in cells transfected with E6*. This is the first report of a potential biological function for this polypeptide and may represent a means by which HPV is able to modulate the activity of the full-length E6 protein with respect to p53 during viral infection.
Pim
D
D
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
Massimi
P
P
Banks
L
L
D017398:Alternative Splicing; D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins; D005260:Female; D005354:Fibrosarcoma; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames; D012516:Osteosarcoma; D027383:Papillomaviridae / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53