Inhibition of E6 induced degradation of p53 is not sufficient for stabilization of p53 protein in cervical tumour derived cell lines.
The E6 proteins derived from tumour associated papillomavirus types target the cellular tumour suppressor protein p53 for ubiquitin mediated degradation. In cell lines derived from cervical tumours the p53 protein is present in very low amounts, but it can be activated by appropriate DNA damaging agents, indicating that functional p53 is present within these lines. Recent studies have also shown that different polymorphic forms of the p53 protein are differentially susceptible to E6 mediated degradation. Therefore we have been interested in analysing the effects of different HPV E6 proteins upon p53 levels in a variety of cervical tumour derived cell lines. We show that inhibition of E6 mediated degradation of p53 frequently results in increased levels of p53 expression. However, there are notable exceptions to this where increased p53 levels are only obtained following DNA damage and proteasome inhibition. We also show in E6 expressing cells, that as well as p53 being targeted for degradation, the localization of p53 to the nucleus is also inhibited, consistent with previous observations which indicate that degradation of p53 is not essential for E6 mediated inhibition of p53 function. These results have important implications for any potential therapies which might aim to block E6 mediated degradation of p53.
Mantovani
F
F
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
Banks
L
L
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000821:virology*; D002467:Cell Nucleus / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism*; D011110:Polymorphism, Genetic; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000821:virology*
D000903:Antibiotics, Antineoplastic; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D007976:Leupeptins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C063261:acetylleucyl-leucyl-norleucinal; C067713:lactacystin; D016685:Mitomycin; D000111:Acetylcysteine