Induction of apoptosis by p53 is independent of its oligomeric state and can be abolished by HPV-18 E6 through ubiquitin mediated degradation.
Inhibition of p53 function is a common feature of many DNA tumour viruses. Human papillomavirus (HPV) E6 proteins from the oncogenic HPVs inhibit p53 function either by blocking its ability to bind DNA or by labelling newly synthesised p53 as a target for ubiquitin mediated degradation. In this study we have investigated the role of the degradation function of E6 with respect to p53 function. Using a panel of previously characterised p53 mutant proteins we have been able to establish a series of assays which separates p53 growth suppression from transformation suppression and from induction of apoptosis. Only wild type p53 inhibits the growth of p53 null 10(1) cells, whereas wild type, dimeric and monomeric mutants of p53 suppress transformed cell growth of both Saos-2 cells and baby rat kidney cells. Cells expressing the different oligomeric forms of p53 all retain the ability to induce apoptosis upon u.v. treatment. Using HPV E6 and E7 we have been able to show that E7 will overcome p53 growth suppressor activity with an efficiency similar to that observed with E6. However, in contrast to E6, E7 has no effect on the ability of p53 to suppress transformed cell growth. Finally, we show that the ability of E6 to label p53 for ubiquitin mediated degradation is prerequisite for its ability to overcome p53 inhibition of transformed cell growth and induction of apoptosis. These observations argue that E6 inhibits p53 mediated apoptosis and suppression of transformation while E7 inhibits p53 suppression of cell proliferation.
Thomas
M
M
International Centre for Genetic Engineering and Biotechnology, AREA Science Park, Trieste, Italy.
Matlashewski
G
G
Pim
D
D
Banks
L
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D011905:Genes, ras; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D014170:Transformation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D014452:Ubiquitins / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins