Differential regulation of cell growth and gene expression by FGF-2 and FGF-4 in pituitary lactotroph GH4 cells.
Fibroblast growth factors, FGF-2 and FGF-4, are reported to play divergent roles in pituitary differentiation and tumor formation, stimulating cell differentiation or proliferation, respectively. However, mitogenic responses to FGFs have not been extensively characterized and little is known about the molecular mechanisms by which specific FGF isoforms may mediate distinct biological responses. Here we show that FGF-4 but not FGF-2 stimulated DNA synthesis and cell proliferation in GH4 cells. Microarray analyses revealed that FGF-4 induced expression of several oncogenes, growth factor receptors and cell cycle control proteins (e.g. cyclin D3/cdk4, N-myc, c-Raf, insulin and thyroid hormone receptors) while FGF-2 had no effect or down regulated these same genes. These transcriptional responses are consistent with a proliferative and/or tumorigenic role for FGF-4 versus a growth inhibitory effect of FGF-2. FGF-2 and FGF-4 also differentially regulated MAP kinase phosphorylation, which may underlie their isoform-specific effects on cell growth and gene expression.
Program in Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center at Fitzsimons, Aurora, CO 80045, USA.
Twila A
TA
Jackson
David M
DM
Koterwas
Andrew P
AP
Bradford
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D051519:Fibroblast Growth Factor 4 / Q000502:physiology*; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction
D018797:Cell Cycle Proteins; D051519:Fibroblast Growth Factor 4; D017978:Receptors, Growth Factor; D016222:Fibroblast Growth Factor 2