Identification of c‐Jun as a critical mediator for the intracrine 24 kDa FGF‐2 isoform‐induced cell proliferation

Abstract

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.

The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: The role of JNK signaling

“…The FGF2 LMW and HMW isoforms have been reported to evoke different biological functions in a variety of cell types [2,12,28]. Transfection of FGF2 isoforms in an osteoblastic cell line showed that neutralizing FGF2 antibodies blocked cell growth in FGF2 LMW overexpressing cells but not in FGF2 HMW isoforms overexpressing cells, suggesting that the FGF2 HMW isoforms modulate cell growth and DNA synthesis by a mechanism independent of its cell surface receptors [29].…”

Trafficking of Nuclear Heparin-Binding Epidermal Growth Factor–like Growth Factor into an Epidermal Growth Factor Receptor–Dependent Autocrine Loop in Response to Oxidative Stress

“…Distinct 18 kDa and 24 kDa FGF-2 isoforms, synthesized from a single mRNA through the use of alternative initiation codons, mediate autocrine/ paracrine and intracrine signaling, respectively (36). Nuclear FGF-2 has been associated with increased tumor cell survival and enhanced metastatic capability in vivo (38), direct regulation of transcription (39) and mRNA splicing (40), and activation of Erk-MAPK signaling, leading to expression of the cell cycle regulator c-Jun (41). The EGFlike growth factors TGF-a and amphiregulin have been reported to reside in nuclei in several cell types, but a specialized role for these nuclear isoforms is still poorly understood.…”

Induction of early response genes in trypsin inhibitor-induced pancreatic growth

“…1D), and Egr-1 (Fig. 1G), which are known to be related to cell proliferation (1,6,16,22,23,34,46). Camostat feeding rapidly upregulated the expression of 17 of 18 early response genes at the mRNA level by 2.4-to 600-fold (Table 1).…”