Identification of c-Jun as a critical mediator for the intracrine 24 kDa FGF-2 isoform-induced cell proliferation.
Tumor cells frequently synthesize an N-terminally extended the FGF-2 isoform of 24 kDa devoid of signal peptide but that contains a functional nuclear localization sequence (NLS). Although the signaling pathways elicited by secreted FGF-2 are well described, the molecular mechanisms involved in the growth promoting action of nuclearized 24 kDa FGF-2 remain unknown. The cancer cell line AR4-2J was engineered to stably express only the 24 kDa FGF-2 isoform and cDNA microarrays were used to identify targets implicated in the intracrine-induced cell proliferation. Levels of 27 transcripts were found either upregulated or downregulated compared to control cells. Among the 18 upregulated genes was c-jun, which is often involved in cell proliferation. Real-time PCR and Western blot analyses confirmed c-jun induction at both mRNA and protein levels. The c-jun antisense oligonucleotide strategy pointed out the involvement of c-Jun in the 24 kDa FGF-2-induced cell proliferation. The mitogenic effect was found to depend on ERK pathway and not on phosphoinositide 3-kinase, p38 MAPK, c-Jun NH2-terminal kinase signal transducers. In addition, the MEK inhibitor PD98059 reduced the 24 kDa FGF-2-dependent c-Jun level. These data show that intracrine FGF-2-mediated regulation of cell growth involves ERK activation and consequent c-Jun expression. Thus, despite its incapacity to be secreted, the intracellular-localized 24 kDa FGF-2 can activate a growth-related signaling pathway normally elicited by cell surface receptors.
Hortala
Marylis
M
INSERM U 531, IFR31, Institut Louis Bugnard, CHU Rangueil Bat L3, TSA 50032, 31059 Toulouse, France.
Estival
Agnes
A
Pradayrol
Lucien
L
Susini
Christiane
C
Clemente
François
F
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense; D010190:Pancreatic Neoplasms / Q000473:pathology; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D016755:Proto-Oncogene Proteins c-jun / Q000494:pharmacology*; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D016755:Proto-Oncogene Proteins c-jun; D016222:Fibroblast Growth Factor 2