Exon III splicing of fibroblast growth factor receptor 1 is modulated by growth factors and cyclin D1.
OBJECTIVE
Fibroblast growth factor receptor 1 (FGFR1) isoform IIIc enhances and FGFR1-IIIb inhibits pancreatic cancer cell growth. Nothing is presently known about the expression and regulation of human FGFR1-III isoforms. The aim of this study was to identify regulators modulating the specific expression of human FGFR1-IIIb and FGFR1-IIIc.


METHODS
Parental cells, cells overexpressing FGFR1-III isoforms, and cells harboring a tetracycline-inducible cyclin D1 antisense expression vector system were used as model systems.


RESULTS
FGFR1-IIIb and -IIIc were coexpressed in human pancreatic cancer cells, with FGFR1-IIIc being the predominant isoform. FGFR1-IIIb mRNA expression decreased at higher cell density, whereas FGFR1-IIIc expression remained constant. Insulinlike growth factor I and epidermal growth factor induced expression of FGFR1-IIIc without altering FGFR1-IIIb. In contrast, fibroblast growth factor (FGF)1, FGF2, and FGF5 induced FGFR1-IIIc and reduced the expression of FGFR1-IIIb. Overexpression of one isoform did not alter the expression of the corresponding FGFR1-III isoform. Inhibition of cyclin D1, known to be induced by insulinlike growth factor I, epidermal growth factor, and FGF2, resulted in an inhibition of FGFR1-IIIc expression, whereas FGFR1-IIIb expression was enhanced.


CONCLUSIONS
This study demonstrated for the first time that FGFR1-IIIb and FGFR1-IIIc are coexpressed and that the FGFR1-III isoformsare differentially regulated by growth factors and cyclin D1.
Chen
Guowei
G
Department of General, Visceral, and Transplantation Surgery, University of Ulm, Ulm, Germany.
Wang
Jian
J
Liu
Zhanbing
Z
Kornmann
Marko
M
D017398:Alternative Splicing / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D051521:Fibroblast Growth Factor 5 / Q000378:metabolism / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*
D017931:DNA Primers; C496449:FGF5 protein, human; D006133:Growth Substances; D020033:Protein Isoforms; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D051521:Fibroblast Growth Factor 5; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1