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Matrix metalloproteinase-3 induction in rat brain astrocytes: focus on the role of two AP-1 elements.

Authors
Kim, KS; Kim, HY; Joe, EH; Jou, I
Citation
The Biochemical journal, 410(3):605-611, 2008
Journal Title
The Biochemical journal
ISSN
0264-60211470-8728
Abstract
Many brain cells secrete MMPs (matrix metalloproteinases), and increased or misregulated MMP levels are found in neurodegenerative disorders. Here we report that MMP-3 transcription and protein secretion were increased in rat brain astrocytes stimulated with lipopolysaccharide, gangliosides or interferon-gamma. Sequential deletion of the MMP-3 promoter revealed that sequences between -0.5 kb and the start codon were crucial for the transcriptional induction of MMP-3. In addition, experiments using pharmacological inhibitors of individual mitogen-activated protein kinases revealed that MMP-3 induction and promoter activity involved Jun N-terminal kinase, a representative upstream signal of AP-1 (activator protein-1). Sequence analyses of the region of the MMP-3 promoter 500 bp from the start codon indicated the presence of three AP-1 binding sequences. Among them, electrophoretic-mobility-shift assays as well as site-directed mutagenesis of individual AP-1 sequences revealed that distal and middle, but not proximal, sequences largely mediated its induction. Together, these results indicate that AP-1 could control MMP-3 induction in brain astrocytes and that its regulation through specific AP-1 elements could be exploited in the treatment of brain pathologies in which increased expression of MMP-3 plays crucial roles.
MeSH terms
AnimalsAstrocytes/enzymology*Base SequenceBlotting, WesternBrain/cytologyBrain/enzymology*DNADNA PrimersElectrophoretic Mobility Shift AssayEnzyme InductionGangliosides/pharmacologyInterferon-gamma/pharmacologyJNK Mitogen-Activated Protein Kinases/metabolismLipopolysaccharides/pharmacologyMatrix Metalloproteinase 3/biosynthesis*Matrix Metalloproteinase 3/geneticsPromoter Regions, GeneticRatsRats, Sprague-DawleyReverse Transcriptase Polymerase Chain ReactionTranscription Factor AP-1/physiology*Transcription, Genetic
DOI
10.1042/BJ20071207
PMID
18072934
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
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