| First Author | Morizane Y | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 18 | Pages | 16030-8 |
| PubMed ID | 21402702 | Mgi Jnum | J:172076 |
| Mgi Id | MGI:5003397 | Doi | 10.1074/jbc.M110.199398 |
| Citation | Morizane Y, et al. (2011) AMP-activated Protein Kinase Suppresses Matrix Metalloproteinase-9 Expression in Mouse Embryonic Fibroblasts. J Biol Chem 286(18):16030-8 |
| abstractText | Matrix metalloproteinase-9 (MMP-9) plays a critical role in tissue remodeling under both physiological and pathological conditions. Although MMP-9 expression is low in most cells and is tightly controlled, the mechanism of its regulation is poorly understood. We utilized mouse embryonic fibroblasts (MEFs) that were nullizygous for the catalytic alpha subunit of AMP-activated protein kinase (AMPK), which is a key regulator of energy homeostasis, to identify AMPK as a suppressor of MMP-9 expression. Total AMPKalpha deletion significantly elevated MMP-9 expression compared with wild-type (WT) MEFs, whereas single knock-out of the isoforms AMPKalpha1 and AMPKalpha2 caused minimal change in the level of MMP-9 expression. The suppressive role of AMPK on MMP-9 expression was mediated through both its activity and presence. The AMPK activators 5-amino-4-imidazole carboxamide riboside and A769662 suppressed MMP-9 expression in WT MEFs, and AMPK inhibition by the overexpression of dominant negative (DN) AMPKalpha elevated MMP-9 expression. However, in AMPKalpha(-/-) MEFs transduced with DN AMPKalpha, MMP-9 expression was suppressed. AMPKalpha(-/-) MEFs showed increased phosphorylation of IkappaBalpha, expression of IkappaBalpha mRNA, nuclear localization of nuclear factor-kappaB (NF-kappaB), and DNA-binding activity of NF-kappaB compared with WT. Consistently, selective NF-kappaB inhibitors BMS345541 and SM7368 decreased MMP-9 expression in AMPKalpha(-/-) MEFs. Overall, our results suggest that both AMPKalpha isoforms suppress MMP-9 expression and that both the activity and presence of AMPKalpha contribute to its function as a regulator of MMP-9 expression by inhibiting the NF-kappaB pathway. |
