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

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.

Transforming Growth Factor-β1 Is a Molecular Target for the Peroxisome Proliferator-Activated Receptor δ

“…34 -36 In addition, autoinduction of the TGF-␤1 gene via the AP-1 site has been reported, 37 and this AP-1 site has been documented to be the most plausible element in transcriptional regulation of the TGF-␤1 gene. 38 In the present study, we identified DR1 as a cis element in the promoter region of the TGF-␤1 gene and demonstrated that it is responsible for PPAR␦-induced upregulation.…”

TNF-α induces TGF-β1expression in lung fibroblasts at the transcriptional levelviaAP-1 activation

“…ERK has been shown to phosphorylate residues of the c-Jun transactivation domain, thereby facilitating AP-1 transcription factor dimerization, DNA binding, and transcriptional regulation [49]. Therefore, we postulated that TNF-␣ activation of the ERK pathway may mediate both AP-1 dependent induction of TGF-␤1 transcription and mRNA stabilization.…”

BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood–brain-barrier

“…Angiogenesis is regulated by multiple positive-and negative-regulatory factors, including vascular endothelial growth factor (VEGF), angiopoitins, interferons (alpha/beta/gamma), IL-12, tissue inhibitory metalloproteinase (TIMP)-3 and transforming growth factor-beta 1 (Campbell et al, 1999;Rivieccio et al, 2005;Zeinstra et al, 2006;Constantinescu et al, 2005;Muir et al, 2002;Dhandapani, 2005;Carmeliet, 2000;Petersen et al, 2005;Sidky and Borden, 1987;Raza and Cornelius, 2000;Dhandapani et al, 2005Dhandapani et al, , 2007. VEGF, a prototypical angiogenic growth factor, regulates cell proliferation, vascular permeability, chemotaxis, and survival of ECs and vasculogenesis and angiogenesis in the developing embryo (Ferrara et al, 2003).…”