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Induction of transforming growth factor‐β1 by basic fibroblast growth factor in rat C6 glioma cells and astrocytes is mediated by MEK/ERK signaling and AP‐1 activation
Author(s) -
Dhandapani Krishnan M.,
Khan Mohammad M.,
Wade F. Marlene,
Wakade Chandramohan,
Mahesh Virendra B.,
Brann Darrell W.
Publication year - 2007
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21182
Subject(s) - basic fibroblast growth factor , mapk/erk pathway , transforming growth factor , glioma , microbiology and biotechnology , fibroblast growth factor , cancer research , biology , signal transduction , growth factor , transforming growth factor beta , mek inhibitor , cell growth , astrocyte , chemistry , endocrinology , receptor , biochemistry , central nervous system
Basic fibroblast growth factor (bFGF) and transforming growth factor‐β1 (TGF‐β1) 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‐β1 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‐β1 release in an isoform‐specific manner. A mediatory role for ERK signaling in bFGF‐induced TGF‐β 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‐β1 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‐β1, suggesting that this pathway may have important implications for brain tumor progression. © 2007 Wiley‐Liss, Inc.