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Differential regulation of JNK activation and MKP-1 expression by peroxovanadium complexes
L Rumora1, A Shaver, T Zanic-Grubisic
1Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Quebec, H3G 1Y6, Montreal, Canada. lada.rumora@fbf.tel.hr
Abstract:
Bisperoxovanadium complexes have been identified as insulinomimetic agents and protein tyrosine phosphatase inhibitors. The aim of the present study was to examine the effects of the most potent bisperoxovanadium complex, potassium bisperoxo (1,10-phenanthroline) oxovanadate (V) [bpV(phen)], on expression and activation of c-jun N-terminal protein kinases (JNK) and on expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in different cell lines. We compared the effects of bpV(phen) with the effects of tumor necrosis factor-alpha (TNF-alpha), a known regulator of JNK phosphorylation and inducer of MKP-1. Treatment with bpV(phen) causes significant and sustained down-regulation of MKP-1 expression both in PC12 and HeLa cells. In contrast, TNF-alpha induces MKP-1 expression in PC12 cells and does not alter MKP-1 expression in HeLa cells. Both bpV(phen) and TNF-alpha induce MKP-1 expression in OVCAR-3 cell line but with different dynamics: TNF-alpha causes transient and bpV(phen) sustained induction of MKP-1 expression. Temporal pattern of level of MKP-1 expression correlates with the regulation of 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 activation 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 stressors, bpV(phen) and TNF-alpha, on MKP-1 expression and JNK phosphorylation are strikingly different, depending on the cell type. These results suggest the possible role of MKP-1 in regulation of JNK phosphorylation in both PC12 and OVCAR-3 cell lines treated with bpV(phen).
Insights
Potassium bisperoxo (1,10-phenanthroline) oxovanadate (V) [bpV(phen)] differentially regulates mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and c-jun N-terminal protein kinases (JNK) phosphorylation across cell types. These effects vary significantly compared to tumor necrosis factor-alpha (TNF-alpha).
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Bisperoxovanadium complexes are known insulinomimetic agents and protein tyrosine phosphatase inhibitors.
- c-jun N-terminal protein kinases (JNK) and mitogen-activated protein kinase phosphatase-1 (MKP-1) are critical signaling molecules involved in cellular stress responses.
- Tumor necrosis factor-alpha (TNF-alpha) is a well-established regulator of JNK phosphorylation and an inducer of MKP-1.
Purpose of the Study:
- To investigate the effects of potassium bisperoxo (1,10-phenanthroline) oxovanadate (V) [bpV(phen)], a potent bisperoxovanadium complex, on the expression and activation of JNK.
- To examine the impact of bpV(phen) on the expression of MKP-1 in various cell lines.
- To compare the cellular responses to bpV(phen) with those induced by TNF-alpha.
Main Methods:
- Treatment of PC12, HeLa, and OVCAR-3 cell lines with bpV(phen) and TNF-alpha.
- Analysis of MKP-1 expression levels.
- Assessment of JNK phosphorylation status.
- Evaluation of JNK expression levels.
Main Results:
- bpV(phen) caused sustained down-regulation of MKP-1 in PC12 and HeLa cells, contrasting with TNF-alpha's induction in PC12 cells and no effect in HeLa cells.
- Both agents induced MKP-1 in OVCAR-3 cells, but bpV(phen) resulted in sustained induction, while TNF-alpha caused transient induction.
- JNK phosphorylation patterns correlated with MKP-1 levels in PC12 cells; however, bpV(phen) did not induce JNK phosphorylation in OVCAR-3 or HeLa cells, unlike TNF-alpha.
- Neither bpV(phen) nor TNF-alpha affected JNK expression in any cell line studied.
Conclusions:
- The effects of bpV(phen) and TNF-alpha on MKP-1 expression and JNK phosphorylation are cell-type dependent.
- MKP-1 may play a role in regulating JNK phosphorylation in PC12 and OVCAR-3 cells treated with bpV(phen).
- This study highlights distinct cellular signaling pathways modulated by vanadium complexes and inflammatory cytokines.