Interferon regulatory factor 4 contributes to transformation of v-Rel-expressing fibroblasts.
The avian homologue of the interferon regulatory factor 4 (IRF-4) and a novel splice variant lacking exon 6, IRF-4DeltaE6, were isolated and characterized. Chicken IRF-4 is expressed in lymphoid organs, less in small intestine, and lungs. IRF-4DeltaE6 mRNA, though less abundant than full-length IRF-4, was detected in lymphoid tissues, with the highest levels observed in thymic cells. IRF-4 is highly expressed in v-Rel-transformed lymphocytes, and the expression of IRF-4 is increased in v-Rel- and c-Rel-transformed fibroblasts relative to control cells. The expression of IRF-4 from retrovirus vectors morphologically transformed primary fibroblasts, increased their saturation density, proliferation, and life span, and promoted their growth in soft agar. IRF-4 and v-Rel cooperated synergistically to transform fibroblasts. The expression of IRF-4 antisense RNA eliminated formation of soft agar colonies by v-Rel and reduced the proliferation of v-Rel-transformed cells. v-Rel-transformed fibroblasts produced interferon 1 (IFN1), which inhibits fibroblast proliferation. Infection of fibroblasts with retroviruses expressing v-Rel resulted in an increase in the mRNA levels of IFN1, the IFN receptor, STAT1, JAK1, and 2',5'-oligo(A) synthetase. The exogenous expression of IRF-4 in v-Rel-transformed fibroblasts decreased the production of IFN1 and suppressed the expression of several genes in the IFN transduction pathway. These results suggest that induction of IRF-4 expression by v-Rel likely facilitates transformation of fibroblasts by decreasing the induction of this antiproliferative pathway.
Hrdlicková
R
R
Section of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712-1095, USA.
Nehyba
J
J
Bose
H R
HR
D000595:Amino Acid Sequence; D000818:Animals; D030161:Avian Proteins; D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002642:Chick Embryo; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D020572:Oncogene Proteins v-rel / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D000099218:Interferon Regulatory Factor-4
D030161:Avian Proteins; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D020572:Oncogene Proteins v-rel; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C435124:IRF4 protein, Gallus gallus