| First Author | Rininger A | Year | 2012 |
| Journal | Cell Death Differ | Volume | 19 |
| Issue | 10 | Pages | 1634-43 |
| PubMed ID | 22522596 | Mgi Jnum | J:204797 |
| Mgi Id | MGI:5543363 | Doi | 10.1038/cdd.2012.41 |
| Citation | Rininger A, et al. (2012) MKP-1 antagonizes C/EBPbeta activity and lowers the apoptotic threshold after ischemic injury. Cell Death Differ 19(10):1634-43 |
| abstractText | 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/EBPbeta), previously shown to have neuroprotective properties. These effects included reduced expression of the full-length C/EBPbeta variant and hypo-phosphorylation at the MEK-ERK1/2-sensitive Thr(188) site. Notably, enforced expression C/EBPbeta rescued cells from MKP-1-induced toxicity. Studies performed in knock-out mice indicate that the MKP-1 activity is required to exclude C/EBPbeta from the nucleus basally, and that MKP-1 antagonizes C/EBPbeta 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/EBPbeta and enhancing both BH3 protein expression and cellular caspase activity. Thus, although manipulation of the MKP-1-C/EBPbeta 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. |
