Egr-1 is necessary for fibroblast growth factor-2-induced transcriptional activation of the glial cell line-derived neurotrophic factor in murine astrocytes.
Glial cell line-derived neurotrophic factor (Gdnf) promotes neurite outgrowth and survival of neuronal cells, but its transcriptional regulation is poorly understood. Here, we sought to investigate the mechanism underlying fibroblast growth factor-2 (FGF2) induction of Gdnf expression in astrocytes. We found that FGF2 stimulation of rat astrocytes induced expression of Egr-1 at a high level. Sequence analysis of the rat Gdnf gene identified three overlapping Egr-1-binding sites between positions -185 and -163 of the rat Gdnf promoter. Transfection studies using a series of deleted Gdnf promoters revealed that these Egr-1-binding sites are required for maximal activation of the Gdnf promoter by FGF2. Chromatin immunoprecipitation analysis indicated that Egr-1 binds to the Gdnf promoter. Furthermore, the induction of Gdnf expression by FGF2 is strongly attenuated both in C6 glioma cells stably expressing Egr-1-specific small interfering RNA and in primary cultured astrocytes from the Egr-1 knock-out mouse. Additionally, we found that stimulation of the ERK and JNK pathways by FGF2 is functionally linked to Gdnf expression through the induction of Egr-1. These data demonstrate that FGF2-induced Gdnf expression is mediated by the induction of Egr-1 through activation of the ERK and JNK/Elk-1 signaling pathways.
Shin
Soon Young
SY
Department of Biomedical Science and Technology, Institute of Biomedical Science & Technology, Konkuk University Hospital, Seoul 143-729, Korea.
Song
Haengseok
H
Kim
Chang Gun
CG
Choi
Yang-Kyu
YK
Lee
Kyoung Sun
KS
Lee
Seung-Jae
SJ
Lee
He-Jin
HJ
Lim
Yoongho
Y
Lee
Young Han
YH
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001665:Binding Sites; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
D051766:Early Growth Response Protein 1; D051100:Glial Cell Line-Derived Neurotrophic Factor; D050807:ets-Domain Protein Elk-1; D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases