Ciliary neurotrophic factor activates JAK/Stat signal transduction cascade and induces transcriptional expression of glial fibrillary acidic protein in glial cells.
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.
Kahn
M A
MA
Department of Neurobiology, UCLA School of Medicine 90024-1764, USA.
Huang
C J
CJ
Caruso
A
A
Barresi
V
V
Nazarian
R
R
Condorelli
D F
DF
de Vellis
J
J
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
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