JNK pathway is required for retinoic acid-induced neurite outgrowth of human neuroblastoma, SH-SY5Y.

Neurite outgrowth is a central event of neuronal differentiation that proceeds in multiple processes requiring various cellular factors. Here we demonstrated that c-Jun N-terminal kinase 1 (JNK1) plays an essential role in RA-induced neurite outgrowth of SH-SY5Y cells. Treatment of SH-SY5Y cells with RA induced a strong activation of JNK1 within 10 min, and the immediate increase of JNK1 activity returned to the basal level in an hour. The second surge of JNK1 activity was observed around 1 day after RA treatment, which coincided with the period of extensive neurite outgrowth. Interestingly, phospho-JNK was concentrated in the nucleus of cells during the early induction, whereas it was distributed into neurite processes during the delayed second activation period. In SH-SY5Y carrying a dominant negative form of SEK1, an upstream kinase of JNK1, both early and late inductions of JNK1 activity were repressed along with RA-induced neurite outgrowth. These results suggest that JNK1 plays an essential role in RA-induced neuronal differentiation of SH-SY5Y cells.