ACTIVATION OF JNK SIGNALING PATHWAY IN RA-INDUCED NEURITE OUTGROWTH 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 differentiation, which include neurotrophins and ERK. 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, which was followed by the second surge occurring around 1 day after RA treatment. The second surge of JNK1 activation was preceded the period of active neuritogenesis. The analysis with SH-SY5Y cell line overexpressing a splicing form of JIP1 (called SKIP-2a), a scaffold protein for JNK signaling pathway suppressing JNK1 activation when overexpressed, revealed a significant inhibition of RA-induced differentiation. 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 also inhibited. These results suggest that JNK1 plays an important role in RA induced neuronal differentiation of SH-SY5Y cells.