Zinc Induces Expression of the BH3-only Protein PUMA Through p53 and ERK Pathways in SH-SY5Y Neuroblastoma Cells

Accumulating evidence suggests that zinc (Zn2+) contributes to neuronal death in pathologic states such as ischemia. p53-upregulated modulator of apoptosis (PUMA), which is a BH3-only protein, is known to promote apoptosis through a tumor suppressor p53-dependent and -independent mechanism. In this study, we examined the effect of Zn2+ on the induction of the PUMA gene in human neuroblastoma SH-SY5Y cells. The expression of PUMA was induced by Zn2+ in a dose- and time-dependent manner. A reporter assay revealed that Zn2+ activated the PUMA promoter. In addition, the mutation of the p53 binding site in the PUMA promoter region reduced promoter activation by Zn2+. These findings suggest that p53 participates in Zn2+-induced PUMA expression. Furthermore, we also demonstrated here that Zn2+ stimulates the phosphorylation of ERK and that the MEK-ERK pathway inhibitor, U0126, suppressed Zn2+-induced PUMA expression. Taken together, these results indicate that Zn2+ regulates the induction of PUMA through p53 and ERK pathways.