Oncogenic potential of the adenovirus E4orf6 protein.
The group C adenovirus E4orf6 protein has previously been shown to bind to the p53 cellular tumor suppressor protein and block its ability to activate transcription. Here we show that the E4orf6 protein blocks the induction of p53-mediated apoptosis when AT6 cells, which harbor a temperature-sensitive p53, are shifted to the permissive temperature. The E4orf6 protein does not, however, prevent the induction of apoptosis in p53-deficient H1299 cells by treatment with tumor necrosis factor alpha and cycloheximide. The E4orf6 protein also cooperates with the adenovirus E1A protein to transform primary baby rat kidney cells, and it cooperates with the adenovirus E1A plus E1B 19-kDa and E1B 55-kDa proteins to increase the number of baby rat kidney cell transformants and enhance the rate at which they arise. The level of p53 is substantially reduced in transformed cells expressing the E4orf6 protein in comparison to adenovirus transformants lacking it. The E4orf6 gene also accelerates tumor formation when transformed baby rat kidney cells are injected subcutaneously into the nude mouse, and it converts human 293 cells from nontumorigenic to tumorigenic in nude mice. In addition to the well-studied E1A and E1B oncogenes, group C adenoviruses harbor a third oncogene, E4orf6, which functions in some respects similarly to the E1B oncogene.
Moore
M
M
Howard Hughes Medical Institute, Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014, USA.
Horikoshi
N
N
Shenk
T
T
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis; D017501:Adenovirus E1B Proteins / Q000096:biosynthesis; D017504:Adenovirus E4 Proteins / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D003513:Cycloheximide / Q000494:pharmacology; D005814:Genes, Viral; D006801:Humans; D007668:Kidney; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000473:pathology; D016133:Polymerase Chain Reaction; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D017504:Adenovirus E4 Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D003513:Cycloheximide