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Identification of c‐Jun as a critical mediator for the intracrine 24 kDa FGF‐2 isoform‐induced cell proliferation
Author(s) -
Hortala Marylis,
Estival Agnes,
Pradayrol Lucien,
Susini Christiane,
Clemente François
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20744
Subject(s) - intracrine , biology , cell growth , mapk/erk pathway , signal transduction , microbiology and biotechnology , autocrine signalling , cell cycle , fibroblast growth factor , cell , receptor , biochemistry
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. © 2004 Wiley‐Liss, Inc.