TGF-β induction of FGF-2 expression in stromal cells requires integrated smad3 and MAPK pathways.
Transforming Growth Factor-β (TGF-β) regulates the reactive stroma microenvironment associated with most carcinomas and mediates expression of many stromal derived factors important for tumor progression, including FGF-2 and CTGF. TGF-β is over-expressed in most carcinomas, and FGF-2 action is important in tumor-induced angiogenesis. The signaling mechanisms of how TGF-β regulates FGF-2 expression in the reactive stroma microenvironment are not understood. Accordingly, we have assessed key signaling pathways that mediate TGF-β1-induced FGF-2 expression in prostate stromal fibroblasts and mouse embryo fibroblasts (MEFs) null for Smad2 and Smad3. TGF-β1 induced phosphorylation of Smad2, Smad3, p38 and ERK1/2 proteins in both control MEFs and prostate fibroblasts. Of these, Smad3, but not Smad2 was found to be required for TGF-β1 induction of FGF-2 expression in stromal cells. ChIP analysis revealed a Smad3/Smad4 complex was associated with the -1.9 to -2.3 kb upstream proximal promoter of the FGF-2 gene, further suggesting a Smad3-specific regulation. In addition, chemical inhibition of p38 or ERK1/2 MAPK activity also blocked TGF-β1-induced FGF-2 expression in a Smad3-independent manner. Conversely, inhibition of JNK signaling enhanced FGF-2 expression. Together, these data indicate that expression of FGF-2 in fibroblasts in the tumor stromal cell microenvironment is coordinately dependent on both intact Smad3 and MAP kinase signaling pathways. These pathways and key downstream mediators of TGF-β action in the tumor reactive stroma microenvironment, may evolve as putative targets for therapeutic intervention.
Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX, USA ; Current address: Department of Urology, University of Texas Southwestern Medical Center Dallas, TX 75390-9110.
Douglas W
DW
Strand
Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX, USA ; Department of Surgery, Baylor College of Medicine Houston, TX, USA.
Yao-Yun
YY
Liang
Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX, USA.
Feng
F
Yang
Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX, USA ; Current address: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center New York City, NY 10065.
David A
DA
Barron
Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX, USA ; Current address: Aptalis Pharmaceuticals 100 Somerset Corporate Blvd, Bridgewater, NJ 08807, USA.
Steven J
SJ
Ressler
Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX, USA ; Current address: Department of Mathematics and Life Sciences, Brazosport College Lake Jackson, TX 77566.
Isaiah G
IG
Schauer
Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX, USA ; Department of Surgery, Baylor College of Medicine Houston, TX, USA.
Xin-Hua
XH
Feng
Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, TX, USA.
David R
DR
Rowley
FGF-2; TGF-β; Tumor microenvironment; promoter regulation; signaling pathway