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- Title
MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury.
- Authors
Rininger, A; Dejesus, C; Totten, A; Wayland, A; Halterman, M W
- Abstract
The dual specificity phosphatase MAPK phosphatase-1 (MKP-1) feeds back on MAP kinase signaling to regulate metabolic, inflammatory and survival responses. MKP-1 is widely expressed in the central nervous system (CNS) and induced after ischemic stress, although its function in these contexts remains unclear. Here we report that MKP-1 activated several cell death factors, including BCL2 and adenovirus E1B 19 kDa interacting protein 3, and caspases 3 and 12 culminating in apoptotic cell death in vitro. MKP-1 also exerted inhibitory effects on the bZIP transcription factor CCAAT/enhancer-binding protein (C/EBPβ), previously shown to have neuroprotective properties. These effects included reduced expression of the full-length C/EBPβ variant and hypo-phosphorylation at the MEK-ERK1/2-sensitive Thr188 site. Notably, enforced expression C/EBPβ rescued cells from MKP-1-induced toxicity. Studies performed in knock-out mice indicate that the MKP-1 activity is required to exclude C/EBPβ from the nucleus basally, and that MKP-1 antagonizes C/EBPβ expression after global forebrain ischemia, particularly within the vulnerable CA1 sector of the hippocampus. Overall, MKP-1 appears to lower the cellular apoptotic threshold by inhibiting C/EBPβ and enhancing both BH3 protein expression and cellular caspase activity. Thus, although manipulation of the MKP-1-C/EBPβ axis could have therapeutic value in ischemic disorders, our observations using MKP-1 catalytic mutants suggest that approaches geared towards inhibiting MKP-1's phosphatase activity alone may be ineffective.
- Subjects
CORONARY disease; ISCHEMIA; APOPTOSIS; CELL death; NEUROPROTECTIVE agents; CASPASES
- Publication
Cell Death & Differentiation, 2012, Vol 19, Issue 10, p1634
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/cdd.2012.41