Activation of JNK signaling pathway in RA-induced neural differentiation of human neuroblastoma, SH-SY5Y

초록

SH-SY5Y is a neuroblast subclone of the neuroblastoma cell line SK-N-SH. SH-SY5Y cells differentiate along a sympathetic chromaffin lineage in response to a morphogen retinoic acid (RA). Several signal transduction pathways are known to be involved in the RA-induced neural differentiaton, which include neurotrophins and ERK MAPK. Here we demonstrated that c-Jun N-terminal kinase (JNK1), a stress activated protein kinase, plays an important role in RA-induced neural differentiation of SH-SY5Y cells. RA treatment of SH-SY5Y cells induces an activation of JNK1 within 10 min, followed by the second surge that occurred around 1-2 days after RA treatment. The second surge of JNK1 activation preceeded the period of active neuritogenesis, suggesting the functional association. The analysis with SH-SY5Y cell line overexpressing a splicing form of JIP1 (called SKIP-2a), a scaffold protein for JNK signaling pathway with the ability to suppress JNK1 activation, revealed a significant inhibition of RA-induced differentiation. As expected, such inhibition was accompanied by the abolishment of the immediate and late induction of JNK1 activation. The involvement of JNK1 signaling pathway was further confirmed by using the SH-SY5Y cells overexpressing dominant negative form of SEK1, an upstream kinase for JNK1, wherein RA-induced neural differentiation and JNK1 activation was similarly inhibited. These results suggest that JNK1 plays a role in RA induced neuronal differentiation of SH-SY5Y cells.