Differential regulation of JNK activation and MKP-1 expression by peroxovanadium complexes

Bisperoxovanadium complexes have been identified as insulinomimetic agents and protein tyrosine phosphatase inhibitors. The aim of the present study w as to examine the effects of the most potent bisperoxovanadium complex, pot assium bisperoxo (1,10-phenanthroline) oxovanadate (V) [bpV(phen)], on expr ession and activation of c-jun N-terminal protein kinases (JNK) and on expr ession of mitogen-activated protein kinase phosphatase-1 (MKP-1) in differe nt cell lines. We compared the effects of bpV(phen) with the effects of tum or necrosis factor-alpha (TNF-alpha), a known regulator of JNK phosphorylat ion and inducer of MKP-1. Treatment with bpV(phen) causes significant and s ustained down-regulation of MKP-1 expression both in PC12 and HeLa cells. I n contrast. TNF-alpha induces MKP-1 expression in PC12 cells and does not a lter MKP-1 expression in HeLa cells. Both bpV(phen) and TNF-alpha induce MK P-1 expression in OVCAR-3 cell line but with different dynamics: TNF-alpha causes transient and bpV(phen) sustained induction of MKP-1 expression. Tem poral pattern of level of MKP-1 expression correlates with the regulation o f JNK phosphorylation by bpV(phen) and TNF-alpha in PC12 cells. However, no detectable phospho-JNK signal is observed in either OVCAR-3 or HeLa cells treated with bpV(phen). In contrast. TNF-alpha causes strong and sustained JNK phosphorylation in OVCAR-3 cell line, and strong but transient JNK acti vation in HeLa cells. BpV(phen) and TNF-alpha does not alter JNK expression in any of the cell lines studied. We demonstrate that the effect of two st ressors, bpV(phen) and TNF-alpha, on MKP-1 expression and JNK phosphorylati on are strikingly different, depending on the cell type. These results sugg est the possible role of MKP-1 in regulation of JNK phosphorylation in both PC12 and OVCAR-3 cell lines treated with bpV(phen). (C) 2001 Elsevier Scie nce Ltd. All rights reserved.