The fibroblast growth factor binding protein (FGF-BP; GenBank accession no. NP_005121) is a secreted protein that mobilizes FGFs from the extracellular matrix, protects them from degradation, and enhances their biological activity. Several previous studies reported that FGF-BP is an early response gene upregulated during tissue repair processes including wound healing and atherogenesis. In this study we analyzed whether FGF-BP expression was impacted by spinal cord injury and could have an effect on neuronal cell viability. Immunohistochemical and in situ hybridization studies revealed a dramatic upregulation of FGF-BP protein and mRNA levels following unilateral hemisection and contusion injury of adult rat spinal cord. In spinal cord sections of laminectomized rats, increased FGF-BP expression was observed in the fibers and cell bodies ipsilateral to the lesion site but was absent in the uninjured spinal cord tissue contralateral to the lesion. Increased expression of FGF-BP was observed at all postinjury time points, examined with peak levels occurring at day 4, a time when injury-induced increased levels of FGF2 have also been reported to be maximal. Moreover, using PC12 cells as a neuronal model, we observed that exogenous FGF-BP increased the capacity of FGF2 to stimulate neurite outgrowth and to increase cell survival. At the molecular level, FGF-BP enhanced FGF2-induced protein tyrosine phosphorylation and AKT/PKB activation. Collectively, these results suggest that FGF-BP is an early response gene after spinal cord injury and that its upregulation in regenerating spinal cord tissue may provide a molecular mechanism for enhancing the initial FGF2-mediated neurotrophic effects occurring after such tissue damage.

The ®broblast growth factor-binding protein (FGF-BP) modulates FGF activity through binding and release from the extracellular matrix. Consequently, the expression of FGF-BP in certain tumor types is a rate-limiting regulator of FGF-mediated angiogenesis. FGF-BP is upregulated in squamous cell carcinoma by treatment with mitogens such as EGF or TPA. In this study, we investigated the regulation of FGF-BP gene expression by serum. Treatment of serum-starved ME-180 cells with fetal bovine serum (FBS) resulted in a rapid increase in steady-state levels of FGF-BP mRNA and in the rate of FGF-BP gene transcription. Serum induction of FGF-BP mRNA was not mediated through EGF receptor activation but was dependent on PKC, as well as ERK kinase (MEK) and p38 MAP kinase activation. Promoter analysis showed that C/EBP is the main promoter element required for the serum response. Unlike EGF-activation of FGF-BP, transcriptional induction by serum is not signi®cantly regulated through the AP-1 or E-box sites in the promoter. These results illustrate di erences between the mechanism of induction in response to serum and EGF. Oncogene (2001) 20, 1730 ± 1738.

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