Rapid induction and Ca(2+) influx-mediated suppression of vitamin D3 up-regulated protein 1 (VDUP1) mRNA in cerebellar granule neurons undergoing apoptosis.

Cerebellar granule neurons (CGNs) grown under depolarizing conditions with high K(+) (HK; 30 mM) undergo apoptosis following replacement of HK by physiological K(+) (5.4 mM). Differential display analysis identified eight genes up-regulated in this paradigm of apoptosis. Vitamin D3 up-regulated protein 1 (VDUP1) mRNA was markedly up-regulated as early as 2 h following HK withdrawal. VDUP1 mRNA was up-regulated in other paradigms of neuronal apoptosis as well both in vitro and in vivo. HK effectively suppressed the up-regulation of VDUP1 mRNA in CGNs undergoing apoptosis via Ca(2+) influx through voltage-dependent L-type Ca(2+) channels, which did not require de novo protein synthesis. The up-regulation occurred in parallel with that of the c-jun transcript and c-jun protein phosphorylation. Moreover, SB203580, p38 mitogen-activated protein kinase inhibitor, suppressed up-regulation of both c-jun and VDUP1 mRNAs, and c-jun phosphorylation in CGNs undergoing apoptosis. IGF-1, one of the neuroprotective agents for CGNs, also inhibited VDUP1 mRNA up-regulation through a phosphoinositide 3 kinase-dependent pathway. These results suggest that the VDUP1 gene is a novel member of early response genes in neuronal apoptosis whose expression is directly regulated by Ca(2+) influx and coordinately regulated with the transcription factor c-jun in CGNs.