Identification and characterization of a novel GGA/C-binding protein, GBP-i, that is rapidly inducible by cytokines.
Immunosuppressive states with accompanying alterations in cytokine profiles have been postulated to play a vital role in the reactivation of viruses from latency. Cytokines regulate gene expression by activating transcription factors via well-characterized signal transduction pathways. In this study, we report the identification of a novel inducible protein, GBP-i, that binds to a double-stranded GGA/C-rich region of the transcriptional control region of the human papovavirus JC virus (JCV), specifically within the origin of viral DNA replication. GBP-i is distinct from previously characterized GC-box-binding proteins with respect to both its sequence specificity and its electrophoretic mobility on native and denaturing gels. GBP-i responds within 90 min to phorbol myristate acetate stimulation; however, unlike typical phorbol myristate acetate-inducible factors, this rapid induction is regulated primarily at the transcriptional level. Further, the induction of GBP-i appears to be widespread and mediated by many inflammatory cytokines, including interleukin-1 beta, tumor necrosis factor alpha, gamma interferon, and transforming growth factor beta. Interestingly, the induced protein acts as a transcriptional repressor in its native context in the JCVL promoter. However, when its binding sequence is transposed to a heterologous promoter, GBP-i appears to function as a transcriptional activator. The data presented here suggest a role for GBP-i in cytokine-mediated induction of viral and cellular genes.
Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
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D001483:Base Sequence; D016207:Cytokines / Q000494:pharmacology*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007577:JC Virus / Q000235:genetics*; D008969:Molecular Sequence Data; D009457:Neuroglia / Q000382:microbiology; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012367:RNA, Viral / Q000096:biosynthesis; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D016207:Cytokines; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012367:RNA, Viral; D014157:Transcription Factors