(NAS Colloquium) Genetic Engineering of Viruses and Viral Vectors (1996) / Chapter Skim
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Oncogenic potential of the adenovirus E4orf6 protein
Oncogenic potential of the adenovirus E4orf6 protein
Pages 11295-11301
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From page 11295... ...
The E40rf6 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 EIA and EIB oncogenes, group C adenoviruses harbor a third oncogene, E40rf6, which functions in some respects similarly to the EIB oncogene.
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From page 11296... ...
The red nuclei from transfected cells expressing the E40rf6 protein display little yellow signal (yellow results from the overlap of green and red signals) , whereas the nuclei of cells that do not express the E40rf6 protein display a green signal indicative of DNA fragmentation, a hallmark of apoptosis.
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From page 11297... ...
Primary baby rat kidney cells were transfected with plasmids expressing the indicated adenovirus proteins and assayed for the formation of foci 30 days later. Cells receiving both E1B proteins were transfected with a plasmid containing the intact E1B transcription unit controlled by its own promoter, while cells receiving only the E1B 19-kDa or E1B 55-kDa protein received plasmids carrying cDNAs controlled by the cytomegalovirus major immediate early promoter.
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From page 11298... ...
Two ElA/ElB19,55 baby rat kidney cell transformants and two ElA/ElB19,55/E4 transformants were tested for their ability to induce tumors in athymic Swiss nude mice (Table 1~. Both transformants expressing the E40rf6 protein produced tumors at the site of injection that were detected by palpation on day 28.
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From page 11299... ...
baby rat kidney cells were labeled for 60 min with l35Slmethionine followed by chase periods, after which immunoprecipitations were performed with the pS3-specific monoclonal antibody 421. After electrophoresis, radioactivity in pS3-specific bands was quantified using a PhosphorImager.
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From page 11300... ...
With continued passage, both gene combinations produced cell lines with similar growth characteristics, but the cells with the E1A plus E40Cf6 genes have presumably undergone selection for mutations in cellular genes that result in more rapid growth. The initially slow growth of ElA/E40rf6 transformants and the potential to more efficiently coselect E1A and E1B genes probably explain why ElA/ElB transformants, rather than ElA/E40rf6 transformants, are routinely isolated after infection of rodent cells.
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From page 11301... ...
Presum ably, the E40rf6 protein antagonizes pS3-dependent apoptosis induced directly by ETA, but it does not prevent pS3 independent apoptosis induced indirectly by the E1A protein when it activates another apoptosis-promoting viral gene in adenovirus-infected cells. Many adenovirus vectors that are being considered for gene delivery in humans contain the E40rf6 coding region.
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