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MKP-1 as a target for pharmacological manipulations in PC12 cell survival
L Rumora1, A Shaver, T Zanic Grubisic
1Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Que, Canada. lada.rumora@fbf.tel.hr
Abstract:
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.
Insights
Dual specificity mitogen-activated protein kinase phosphatase-1 (MKP-1) enhances cell survival by increasing ERK phosphorylation. Combining FK506 and peroxovanadium compounds boosts MKP-1 expression and prolongs ERK activation, promoting PC12 cell survival.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Dual specificity mitogen-activated protein kinase phosphatase-1 (MKP-1) regulates mitogen-activated protein kinases (MAPKs) like ERK, p38, and JNK through dephosphorylation.
- MAPKs play critical roles in cellular processes, including survival, proliferation, and differentiation.
- Understanding MKP-1's role in cell survival is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of MKP-1 expression and MAPK phosphorylation in PC12 cell survival.
- To assess the effects of FK506 and monoperoxovanadium complexes (mpVs) on MKP-1 and MAPKs.
Main Methods:
- PC12 cells were treated with FK506 and/or mpVs to manipulate MKP-1 expression.
- Western blotting or similar techniques were used to analyze the phosphorylation status of ERK and JNK.
- Cell survival assays were performed to quantify the effects of the treatments.
Main Results:
- Peroxovanadium compounds activated JNK and decreased MKP-1 expression, while FK506 had a transient effect on ERK.
- Combined treatment with mpVs and FK506 prolonged and intensified ERK phosphorylation.
- This combination therapy significantly increased MKP-1 expression and enhanced PC12 cell survival.
Conclusions:
- Combined administration of monoperoxovanadium complexes and FK506 promotes PC12 cell survival.
- This survival enhancement is mediated by the induction of MKP-1 expression and sustained ERK activation.