title: A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells.
abstract: We have previously demonstrated that the active form of matrix metalloproteinase-3 (actMMP-3) is released from dopamine(DA)rgic neurons undergoing apoptosis. Herein, whether actMMP-3 might be generated intracellularly, and if so, whether it is involved in apoptosis of DArgic neurons itself was investigated in primary cultured DArgic neurons of wild-type, MMP-3 knockout animals, and CATH.a cells. During apoptosis, gene expression of MMP-3 is induced, specifically among the various classes of MMPs, generating the proform (55 kDa) which is subsequently cleaved to the catalytically active actMMP-3 (48 kDa) involving a serine protease. Intracellular actMMP-3 activity is directly linked to apoptotic signaling in DArgic cells: (i) Pharmacologic inhibition of enzymatic activity, repression of gene expression by siRNA, and gene deficiency all lead to protection; (ii) pharmacologic inhibition causes attenuation of DNA fragmentation and caspase 3 activation, the indices of apoptosis; and (iii) inhibition of the pro-apoptotic enzyme c-Jun N-terminal protein kinase leads to repression of MMP-3 induction. Under the cell stress condition, MMP-3 is released as actMMP-3 rather than the proform (proMMP-3), and catalytically active MMP-3 added to the medium does not cause cell death. Thus, actMMP-3 seems to have a novel intracellular role in apoptotic DArgic cells and this finding provides an insight into the pathogenesis of Parkinson's disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Dong Hee
authors.initials: DH
authors.lastname: Choi
authors.forename: Eun-Mee
authors.initials: EM
authors.lastname: Kim
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Son
authors.forename: Tong H
authors.initials: TH
authors.lastname: Joh
authors.forename: Yoon Seong
authors.initials: YS
authors.lastname: Kim
authors.forename: Donghou
authors.initials: D
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Flint Beal
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D020134:Catalytic Domain / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D007424:Intracellular Fluid / Q000201:enzymology*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D048055:Mitogen-Activated Protein Kinase 8; D012697:Serine Endopeptidases; D019278:Matrix Metalloproteinase 3; D004298:Dopamine