p53 activity during adenovirus infection

摘要: Adenovirus is a small DNA tumour virus that has been extensively studied, leading to fundamental discoveries in molecular biology of mammalian cells. In particular, adenovirus oncoproteins were shown inactivate cellular suppressor pathways and this advanced our understanding mechanisms cancer formation. p53 key ensures genomic integrity. Its function impaired most human malignancies, viruses evolved multiple ways block activity favour productive infection. Human type 5 codes for two oncoproteins, E1B-55 kDa E4-34 bind forward degradation proteasomes. Deletion or mutation leads massive accumulation the protein infected Based on fact, an idea p53-selective replicating oncolytic treatment was proposed. It assumed infection cells containing mutant null with E1B-deficient should allow unrestricted replication cell lysis. contrast, normal cells, bearing wild p53, expected such mutants, since functional induce cycle arrest apoptosis after This attractive implemented by creation kDa-deleted virus, designated ONYX-015. However, spite moderate successes head neck treatment, ONYX-015 did not become breakthrough therapy. As numerous studies later, independent status, though indeed, replicated better some as compared The reason failure understood level, when carefully examined became clear that, despite blocked its transcriptional thus prevented induction Therefore, we speculated addition kDa, back up inactivation investigated study. First all, show here E1B-defective mutants induces without obvious defects localization, phosphorylation, conformation, oligomerization. Nonetheless, completely failed target genes, e. g. p21/CDKN1A, mdm2, PUMA. Secondly, found E1A proteins be responsible blocking absence kDa. Two regions gene products independently contributed suppression. Depending conserved region 3 (CR3), transcription ability factor Sp1 p21 promoter. Moreover, aminoterminal E1A, binding acetyltransferases p300 CBP, K382 acetylation Mutating either these regions, E1B, partially restored activity. We conclude inactivates at least E1B-independent mechanisms. Thus, study provides mechanistic explanation why lack cannot result cytotoxicity. described here, taken into account, attempting create Our findings may also help understand attenuation other species virus-independent