title: In adenovirus type 12 tumorigenic cells, major histocompatibility complex class I transcription shutoff is overcome by induction of NF-kappaB and relief of COUP-TFII repression.
abstract: The surface levels of major histocompatibility complex class I antigens are diminished on tumorigenic adenovirus type 12 (Ad12)-transformed cells, enabling them to escape from immunosurveillant cytotoxic T lymphocytes (CTLs). This is due to the down-regulation of the class I transcriptional enhancer, in which there is strong binding of the repressor COUP-TFII and lack of binding of the activator NF-kappaB. Even though NF-kappaB (p65/p50) translocates to the nuclei of Ad12-transformed cells, it fails to bind to DNA efficiently due to the hypophosphorylation of the p50 subunit. In this study, tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) were shown to promote degradation of the NF-kappaB cytoplasmic inhibitor IkappaBalpha and permit the nuclear translocation of a phosphorylated form of NF-kappaB that is capable of binding DNA. Interestingly, when Ad12-transformed cells were treated with TNF-alpha or IL-1beta, class I gene transcription substantially increased when transcriptional repression by COUP-TFII was blocked. This indicates that in cytokine-treated Ad12-transformed cells, COUP-TFII is able to repress activation of class I transcription by newly nucleus-localized NF-kappaB. Our results suggest that Ad12 likely employs a "fail-safe" mechanism to ensure that the transcription of class I genes remains tightly repressed under various physiological conditions, thus providing tumorigenic Ad12-transformed cells with a means of escaping CTL recognition and lysis.
authors.affiliation: Department of Microbiology, School of Dental Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shihe
authors.initials: S
authors.lastname: Hou
authors.forename: Hancheng
authors.initials: H
authors.lastname: Guan
authors.forename: Robert P
authors.initials: RP
authors.lastname: Ricciardi
mesh_terms: D000256:Adenoviridae; D000818:Animals; D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000494:pharmacology; D015536:Down-Regulation; D005805:Genes, MHC Class I; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011987:Receptors, Steroid; D012097:Repressor Proteins / Q000378:metabolism*; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606206:Nfkbia protein, rat; C497588:Nr2f2 protein, rat; D011987:Receptors, Steroid; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha