AMP-activated protein kinase suppresses matrix metalloproteinase-9 expression in mouse embryonic fibroblasts

Yuki Morizane, Aristomenis Thanos, Kimio Takeuchi, yusuke murakami, Maki Kayama, George Trichonas, Joan Miller, Marc Foretz, Benoit Viollet, Demetrios G. Vavvas

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Abstract

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 α 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 AMPKα deletion significantly elevated MMP-9 expression compared with wild-type (WT) MEFs, whereas single knock-out of the isoforms AMPKα1 and AMPKα2 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) AMPKα elevated MMP-9 expression. However, in AMPKα-/- MEFs transduced with DN AMPKα, MMP-9 expression was suppressed. AMPKα-/- MEFs showed increased phosphorylation of IκBα, expression of IκBα mRNA, nuclear localization of nuclear factor-κB (NF-κB), and DNA-binding activity of NF-κB compared with WT. Consistently, selective NF-κB inhibitors BMS345541 and SM7368 decreased MMP-9 expression in AMPKα-/- MEFs. Overall, our results suggest that both AMPKα isoforms suppress MMP-9 expression and that both the activity and presence of AMPKα contribute to its function as a regulator of MMP-9 expression by inhibiting the NF-κB pathway.

Original languageEnglish
Pages (from-to)16030-16038
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number18
DOIs
Publication statusPublished - May 6 2011

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AMP-Activated Protein Kinases
Matrix Metalloproteinase 9
Fibroblasts
A 769662
Protein Isoforms
Phosphorylation
Catalytic Domain
Homeostasis

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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AMP-activated protein kinase suppresses matrix metalloproteinase-9 expression in mouse embryonic fibroblasts. / Morizane, Yuki; Thanos, Aristomenis; Takeuchi, Kimio; murakami, yusuke; Kayama, Maki; Trichonas, George; Miller, Joan; Foretz, Marc; Viollet, Benoit; Vavvas, Demetrios G.

In: Journal of Biological Chemistry, Vol. 286, No. 18, 06.05.2011, p. 16030-16038.

Research output: Contribution to journalArticle

Morizane, Y, Thanos, A, Takeuchi, K, murakami, Y, Kayama, M, Trichonas, G, Miller, J, Foretz, M, Viollet, B & Vavvas, DG 2011, 'AMP-activated protein kinase suppresses matrix metalloproteinase-9 expression in mouse embryonic fibroblasts', Journal of Biological Chemistry, vol. 286, no. 18, pp. 16030-16038. https://doi.org/10.1074/jbc.M110.199398
Morizane, Yuki ; Thanos, Aristomenis ; Takeuchi, Kimio ; murakami, yusuke ; Kayama, Maki ; Trichonas, George ; Miller, Joan ; Foretz, Marc ; Viollet, Benoit ; Vavvas, Demetrios G. / AMP-activated protein kinase suppresses matrix metalloproteinase-9 expression in mouse embryonic fibroblasts. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 18. pp. 16030-16038.
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