ALTERNATIVELY SPLICED HPV-18 E6-ASTERISK PROTEIN INHIBITS E6 MEDIATEDDEGRADATION OF P53 AND SUPPRESSES TRANSFORMED-CELL GROWTH

The E6 proteins originating from the tumour-associated Human Papilloma virus (HPV) types 16 and 18 have been shown to bind to and target the tumour suppressor protein, p53, for ubiquitin-mediated degradation. Ho wever, 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 bot h with the full-length E6 proteins from HPV-16 and HPV-18 and also wit h E6-AP, and subsequently blocks the association of full length E6 pro tein with p53. We also show that, as a result of this block, E6 can i nhibit E6-mediated degradation of p53 both in vitro and in vivo. The b iological 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 biologic al function for this polypeptide and may represent a means by which HP V is able to modulate the activity of the full-length E6 protein with respect to p53 during viral infection.