title: MKP-1 antagonizes C/EBPβ activity and lowers the apoptotic threshold after ischemic injury.
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 Thr(188) 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.
authors.affiliation: Department of Pediatrics, University of Rochester Medical Center, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rininger
authors.forename: C
authors.initials: C
authors.lastname: Dejesus
authors.forename: A
authors.initials: A
authors.lastname: Totten
authors.forename: A
authors.initials: A
authors.lastname: Wayland
authors.forename: M W
authors.initials: MW
authors.lastname: Halterman
mesh_terms: D000818:Animals; D017209:Apoptosis; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053454:Caspase 12 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: C508686:BNip3 protein, mouse; D022782:CCAAT-Enhancer-Binding Protein-beta; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D053454:Caspase 12; D053148:Caspase 3