MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

• Published in: Cell death and differentiation Vol. 19; no. 10; pp. 1634 - 1643
• Main Authors: Rininger, A, Dejesus, C, Totten, A, Wayland, A, Halterman, M W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2012; Nature Publishing Group
• Subjects: 631/443/592/1939; 631/80/82/23; 631/80/86; 692/700/565; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caspase 12 - metabolism; Caspase 3 - metabolism; CCAAT-Enhancer-Binding Protein-beta - antagonists & inhibitors; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Biology; Cell Cycle Analysis; Cell Hypoxia; Cell Line; Dual Specificity Phosphatase 1 - deficiency; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Life Sciences; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Proteins - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Original Paper; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Stem Cells; Transcriptional Activation; neuron; C/EBP; hypoxia; phosphatase; MKP-1; ischemia
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2012.41

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/EBP β ), previously shown to have neuroprotective properties. These effects included reduced expression of the full-length C/EBP β variant and hypo-phosphorylation at the MEK-ERK1/2-sensitive Thr 188 site. Notably, enforced expression C/EBP β rescued cells from MKP-1-induced toxicity. Studies performed in knock-out mice indicate that the MKP-1 activity is required to exclude C/EBP β from the nucleus basally, and that MKP-1 antagonizes C/EBP β 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/EBP β and enhancing both BH3 protein expression and cellular caspase activity. Thus, although manipulation of the MKP-1-C/EBP β 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.