title: Ciliary neurotrophic factor activates JAK/Stat signal transduction cascade and induces transcriptional expression of glial fibrillary acidic protein in glial cells.
abstract: In recent reports, ciliary neurotrophic factor (CNTF) has been implicated as an injury factor involved in regulating astrogliosis in the CNS. In this study, we used a rat oligodendroglial progenitor cell line that is highly responsive to CNTF to examine CNTF-induced alterations that may play a role in activation of the glial fibrillary acidic protein (GFAP) gene. We determined that CNTF induces the transient translocation of Stat1 alpha/p91 to the nucleus. This nuclear translocation was followed by GFAP promoter activation and an up-regulation of GFAP mRNA and protein. Level of CNTF-alpha receptor mRNA, however, were unaffected by addition of the ligand. Transfection studies using an upstream 5'-flanking, 1.9-kb rat GFAP promoter linked to a luciferase reporter gene revealed CNTF-induced transcriptional activation within 1 h of ligand exposure. Moreover, serial-deleted constructs identified a distal (-1,857 to -1,546 bp) and a proximal (-384 to -106 bp) region as being important for CNTF-induced GFAP promoter activation. These two regions showed a strong degree of overlap for CNTF- and serum-induced activation of the GFAP gene. Analysis of the two regions revealed several cis-elements that are thought to be involved in GFAP regulation and/or the regulation of other genes by members of the interleukin-6 family of cytokines. Moreover, we are the first to report the presence of several putative CNTF-responsive elements within our identified distal and proximal regions in the GFAP gene promoter.
authors.affiliation: Department of Neurobiology, UCLA School of Medicine 90024-1764, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Kahn
authors.forename: C J
authors.initials: CJ
authors.lastname: Huang
authors.forename: A
authors.initials: A
authors.lastname: Caruso
authors.forename: V
authors.initials: V
authors.lastname: Barresi
authors.forename: R
authors.initials: R
authors.lastname: Nazarian
authors.forename: D F
authors.initials: DF
authors.lastname: Condorelli
authors.forename: J
authors.initials: J
authors.lastname: de Vellis
mesh_terms: D000209:Acute-Phase Proteins / Q000502:physiology; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D015152:Blotting, Northern; D002460:Cell Line / Q000737:chemistry / Q000502:physiology; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins / Q000502:physiology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D053613:Janus Kinase 1; D008156:Luciferases; D016296:Mutagenesis / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009836:Oligodendroglia / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection
chemical_list: D000209:Acute-Phase Proteins; D001798:Blood Proteins; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; D053613:Janus Kinase 1