Transitory FGF Treatment Results in the Long-Lasting Suppression of the Proliferative Response to Repeated FGF Stimulation

FGF applied as a single growth factor to quiescent mouse fibroblasts induces a round of DNA replication, however continuous stimulation results in arrest in the G1 phase of the next cell cycle. We hypothesized that FGF stimulation induces the establishment of cell memory, which prevents the proliferative response to repeated or continuous FGF application. When a 2-5 days quiescence period was introduced between primary and repeated FGF treatments, fibroblasts failed to efficiently replicate in response to secondary FGF application. The establishment of FGF memory during the first FGF stimulation did not require DNA synthesis, but was dependent on the activity of FGF receptors, MEK, p38 MAPK and NFB signaling, and protein synthesis. While secondary stimulation resulted in strongly decreased replication rate, we did not observe any attenuation of morphological changes, Erk1/2 phosphorylation and cyclin D1 induction. However, secondary FGF stimulation failed to induce the expression of cyclin A, which is critical for the progression from G1 to S phase. Treatment of cells with a broad range histone deacetylase inhibitor during the primary FGF stimulation rescued the proliferative response to the secondary FGF treatment suggesting that the establishment of FGF memory may be based on epigenetic changes. We suggest that FGF memory can prevent the hyperplastic response to cell damage and inflammation, which are associated with an enhanced FGF production and secretion. FGF memory may present a natural obstacle to the efficient application of recombinant FGFs for the treatment of ulcers, ischemias, and wounds. J. Cell. Biochem. 115: 874-888, 2014. (c) 2013 Wiley Periodicals, Inc.