Figure 9.

Putative molecular mechanisms mediating the induction of TrkC expression by VPA in human neuroblastoma cells. The diagram illustrates that VPA enhances the expression of the NTRK3 gene encoding TrkC through the following mechanisms: (a) epigenetic changes involving RUNX3 derepression as the consequence of HDAC inhibition and EZH2 depletion [32,42]; (b) activation of ERK1/2 and JNK signaling pathways. ERK1/2 activation exerts a major stimulatory input on NTRK3 activation by inducing Egr1 expression likely via Elk-1 phosphorylation. The stimulation of JNK appears to provide a minor contribution possibly by participating in Elk-1 phosphorylation.