Changes in NF-kappa B and ISGF3 DNA binding activities are responsible for differences in MHC and beta-IFN gene expression in Ad5- versus Ad12-transformed cells.
Changes in MHC class I expression are frequently observed in tumors, which represents at least one mechanism by which tumor cells escape immune surveillance. MHC class I expression is often suppressed in type 12 adenovirus (Ad12)-transformed rodent cells, but is highly induced in Ad5-transformed cells. This difference helps to explain why Ad12 but not Ad5 can induce tumors in immunocompetent syngeneic rats. In this report we demonstrate that only Ad5- but not Ad12-transformed rodent fibroblasts constitutively express beta-IFN which results in ISGF3 factor induction, and stimulation of MHC class I expression. Furthermore, we demonstrate that in contrast to Ad12-transformed cells, Ad5-transformed cells show constitutive levels of nuclear NF-kappa B-like DNA binding activity. This is of particular interest since both the beta-IFN and the MHC class I promoters contain an NF-kappa B DNA binding site. Thus, high levels of MHC class I expression in Ad5-transformed cells are due to a combinatorial stimulation of two cis-regulatory sequences of the MHC class I promoter: the NF-kappa B binding site and the interferon stimulated response element (ISRE), which binds the ISGF3 factor complex. The failure of Ad12-transformed cells to activate this pathway explains their low levels of MHC class I expression and their greater oncogenicity.
Nielsch
U
U
Laboratory of Molecular Cell Biology, Rockefeller University, New York, NY 10021.
Zimmer
S G
SG
Babiss
L E
LE
D000260:Adenoviruses, Human / Q000235:genetics; D000261:Adenoviruses, Simian / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D005805:Genes, MHC Class I; D005814:Genes, Viral; D050832:Interferon-Stimulated Gene Factor 3; D016899:Interferon-beta / Q000235:genetics*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050832:Interferon-Stimulated Gene Factor 3; D016328:NF-kappa B; D012333:RNA, Messenger; D014157:Transcription Factors; D016899:Interferon-beta; D004247:DNA