title: Induction of transforming growth factor-beta1 by basic fibroblast growth factor in rat C6 glioma cells and astrocytes is mediated by MEK/ERK signaling and AP-1 activation.
abstract: Basic fibroblast growth factor (bFGF) and transforming growth factor-beta1 (TGF-beta1) play an important role in proliferation, differentiation, and survival of malignant gliomas and in normal glial cell biology. Because of these critical roles, potential interactions between these key growth factors were investigated. We previously demonstrated that bFGF potently stimulates TGF-beta1 release from rat glioma cells. The purpose of the present study was to elucidate the mechanism(s) of this regulatory effect, establish its functional importance, and examine whether it extends to nontransformed rat hypothalamic astrocytes (RHA). The results revealed that RHA express the high-affinity FGF(1-4) receptors, and similarly to glioma cells, bFGF stimulated TGF-beta1 release in an isoform-specific manner. A mediatory role for ERK signaling in bFGF-induced TGF-beta release was suggested by the fact that MEK1 inhibition prevented this effect. Additionally, bFGF enhanced MEK1/2 phosphorylation and ERK activation/nuclear translocation, which culminated in increased activity of AP-1-mediated gene transcription. bFGF markedly induced TGF-beta1 mRNA levels in an isoform-specific manner, an effect that was dependent on MEK/ERK/AP-1 signaling. Functionally, bFGF-induced proliferation of glioma cells was attenuated by MEK/ERK inhibition or immunoneutralization of TGF-beta1, suggesting that this pathway may have important implications for brain tumor progression.
authors.affiliation: Department of Neurosurgery, School of Medicine, Medical College of Georgia, Augusta, Georgia, USA. kdhandapani@mcg.edu
authors.forename: Krishnan M
authors.initials: KM
authors.lastname: Dhandapani
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Khan
authors.forename: F Marlene
authors.initials: FM
authors.lastname: Wade
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Wakade
authors.forename: Virendra B
authors.initials: VB
authors.lastname: Mahesh
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases