MKP-1 as a target for pharmacological manipulations in PC12 cell survival.
Dual specificity mitogen activated protein kinase phosphatase-1 (MKP-1) inactivates extracellular signal-regulated kinase (ERK), p38 and/or c-jun N-terminal protein kinase (JNK) by dephosphorylation via a negative feed-back loop. The aim of the present study was to assess the role of expression of MKP-1 and phosphorylation status of mitogen-activated protein kinases (MAPKs) in promoting cell survival in PC12 cells. We used FK506 and three different monoperoxovanadium complexes (mpVs) as pharmacological tools for manipulation of MKP-1 expression. Peroxovanadium compounds, known to be insulinomimetic agents and protein tyrosine phosphatase inhibitors, are cytotoxic to the cells, they activate JNK and down-regulate MPK-1. On the other hand, FK 506 has transient effect on ERK activation. However, when the agents are used in combination, ERK phosphorylation is prolonged and intensified, MKP-1 expression is increased, and cell survival is enhanced. The concomitant alterations observed in intensities and duration of phospho-ERKs and phospho-JNKs signals suggest that monoperoxovanadium complexes in combination with FK 506 enhance survival of PC12 cells by an induction of MKP-1 expression.
Rumora
L
L
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Que, Canada. lada.rumora@fbf.tel.hr
Shaver
A
A
Zanic Grubisic
T
T
Maysinger
D
D
D000818:Animals; D018797:Cell Cycle Proteins; D002470:Cell Survival; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D017874:Immediate-Early Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology; D017968:Vanadium Compounds / Q000494:pharmacology
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D017968:Vanadium Compounds; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; D016559:Tacrolimus