Matrix metalloproteinase‐2 (MMP‐2) is present in the nucleus of cardiac myocytes and is capable of cleaving poly (ADP‐ribose) polymerase (PARP) in vitro

Kwan, Jennifer; Schulze, C.; Wang, Wenjie; León, Hernando; Sarıahmetoğlu, Meltem; Sung, Miranda M.; Sawicka, Jolanta; Sims, David E.; Sawicki, Grzegorz; Schulz, Richard

doi:10.1096/fj.02-1202fje

Cited by 237 publications

(243 citation statements)

References 37 publications

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“…Intracellular existence of matrix metalloproteinase and its activation under various conditions have been reported (23,32,33). In the previous study, we demonstrated that MMP3 is activated in DA cells treated with 1-methyl-4-phenylpyridinium, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-mediated DA neuronal degeneration in the mouse SN was largely attenuated in Mmp3 null mice (22).…”

Section: Discussionmentioning

confidence: 80%

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

Choi

Kim

et al. 2011

Journal of Biological Chemistry

103

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Evidence suggests that the C-terminal truncation of ␣-synuclein is equally important as aggregation of ␣-synuclein in Parkinson disease (PD). Our previous results showed that an endopeptidase, matrix metalloproteinase-3 (MMP3), was induced and activated in dopaminergic (DA) cells upon stress conditions. Here, we report that MMP3 cleaved ␣-synuclein in vitro and in vivo and that ␣-synuclein and MMP3 were co-localized in Lewy bodies (LB) in the postmortem brains of PD patients. Incubation of ␣-synuclein with the catalytic domain of MMP3 (cMMP3) resulted in generation of several peptides, and the peptide profiles of WT ␣-synuclein (WTsyn) and A53T mutant (A53Tsyn) were different. Combined analysis using mass spectrometry and N-terminal determination revealed that MMP3 generated C-terminally truncated peptides of amino acids 1-78, 1-91, and 1-93 and that A53Tsyn produced significantly higher quantities of these peptides. Similar sizes of peptides were detected in N27 DA cells under oxidative stress and RNA interference to knock down MMP3-attenuated peptide generation. Co-overexpression of cMMP3 with either WTsyn or A53Tsyn led to a reduction in Triton X-100-insoluble aggregates and an increase in protofibril-like small aggregates. In addition, overexpression of the 1-93-amino acid peptide in the substantia nigra led to DA neuronal loss without LB-like aggregate formation. The results strongly indicate that MMP3 digestion of ␣-synuclein in DA neurons plays a pivotal role in the progression of PD through modulation of ␣-synuclein in aggregation, LB formation, and neurotoxicity.The epidemiological as well as animal studies suggest that environmental factors, genetic predispositions, and the interplay between the two factors are implicated in the PD 3 pathogenesis (1), although the underlying molecular mechanisms remain largely unknown. ␣-Synuclein is a major component of Lewy bodies (LB), the pathological hallmark of Parkinson disease (2). As expression of three mutant forms of ␣-synuclein, A53T, A30P, and E46K, in the brain (3-5) and increased copy number by duplication or triplication of the wild-type ␣-synuclein gene (6 -8) have been reported in the early onset familial cases of PD, the pathophysiological role of these mutants of ␣-synuclein has been a target of extensive investigations in PD research. The ability of ␣-synuclein to aggregate and form fibrillar deposits has been shown to play a central role in its pathology. The facts that the presence of C-terminally truncated ␣-synuclein in LB of sporadic PD and LB dementia (9, 10), the existence of various lengths of the truncated forms of ␣-synuclein in brain (10, 11), and the formation of C-terminally truncated ␣-synuclein in A53T transgenic mice that show motor symptoms (12) implicate the probable involvement of endopeptidases in cleaving ␣-synuclein in brains. In addition, about 15% of ␣-synuclein in LB are truncated forms, and incomplete degradation of ␣-synuclein produced highly amyloidogenic fragments (9, 13). Recent reports showed that matrix metalloprotei...

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Section: Discussionmentioning

confidence: 80%

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

Choi

Kim

et al. 2011

Journal of Biological Chemistry

103

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“…Poly (ADP-ribose) polymerase (PARP) yes (Kwan et al, 2004) Pregnancy zone protein yes yes (Arbelaez et al, 1997) Pro-IL-1β yes yes (Schonbeck et al, 1998) Pro-IL-8 yes…”

Section: (Van Den Steen Et Al 2000)mentioning

confidence: 99%

“…An interesting observation is that TIMP-1, in addition to the extracellular milieu, can also be found in the nucleus (Zhao et al, 1998), and may even be specifically translocated there from the cell membrane (Ritter et al, 1999). Recently, also MMP-2 was found to be present in the nucleus, and a pro-apoptotic nuclear protein, poly (ADP-ribose) polymerase was cleaved by MMP-2 in vitro suggesting that MMP-2 could partially substitute for caspases in the apoptotic cascade (Kwan et al, 2004). Fotouhi et al, 1994) CTTHWGFTLC peptide catalytic activity TSRI265 docking of MMP-2 to αVβ3 integrin a note that the lack of other inhibitable targets may indicate that the compound has not been tested for inhibition of other proteinases.…”

Section: Gelatinase Inhibitors Naturally Occuring Gelatinase Inhibitorsmentioning

confidence: 99%

Gelatinase-mediated migration and invasion of cancer cells

Björklund

Koivunen

2005

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

465

609

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“…Metaloproteínases da matriz extracelular (MMPs) são uma família de endopeptidases zinco-dependentes conhecidas por degradar componentes do tecido conjuntivo em processos fisiológicos e patológicos (Kwan, Schulze et al 2004). As…”

Section: Metaloproteínases Da Matriz Extracelularunclassified

“…As MMPs são responsáveis pela degradação de muitos componentes da ECM, tais como colágeno, caseína, fibronectina, elastina, laminina e proteoglicana (Aimes and Quigley 1995;Kwan, Schulze et al 2004;Page-McCaw, Ewald et al 2007). Elas são descritas em eventos fisiológicos tais como: desenvolvimento embrionário, morfogênese, reprodução, reabsorção e remodelamento tecidual (Gross and Lapiere 1962).…”

Section: Figuraunclassified

Concentrações de MMP-8, MMP-9, MPO, TIMP-1 e TIMP-2 na saliva e correlações com plasma

Meschiari¹

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Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases known to cleave components of the connective tissue in physiological and pathological processes. The regulation of MMP activities is done by the tissue inhibitors of metalloproteinases (TIMPs).Periodontal disease (PD) is a chronic inflammation with excessive activity of MMPs, which degrade the tooth supporting tissues.The saliva components are derived from the local blood supply, and this fluid may therefore reflect the plasma. So, the objectives of this study were: 1) to compare the levels of MMPs, TIMPs and MPO in stimulated whole saliva (SWS) and plasma of PD patients before (PB) and 3 months after (PT) the non-surgical periodontal treatment, and in healthy volunteers at baseline (CB) and 3 months after baseline (CT), and 2) to evaluate the correlations between the results found.Measurements of MMP-8, MMP-9, TIMP-1 and TIMP-2 were performed by ELISA. Gelatinolitic activity of MMP-9 forms were determined by zymography, and the MPO activity was determined by colorimetric assay.There was lower gelatinolitic activity, and lower concentrations of MMP-8 and TIMP-2 in STE on PT group compared with PB group (p <0.05). MPO activity was higher in PB compared to CB (p <0.05).Statistically significant moderate correlations were observed in all associations between MMP-9 performed by ELISA in plasma and gelatinolitic activity bands of STE: MMP-9 molecular form of 92 kDa (r = 0,37, p = 0,0017), MMP-9 molecular form of 130 kDa (r = 0,35, p = 0,003), the sum of its gelatinase activity (130 +92 kDa) (r = 0,43, p = 0,0002), gelatinase of 180 kDa (r = 0,35, p = 0,003), and the sum of total gelatinase activity (180+130+92 kDa) (r = 0,37, p = 0,002). Circulating MMP-8 levels correlate with salivary gelatinase activity bands of 92 kDa (r = 0,30, p = 0,01) and the sum of gelatinase activity (130 +92 kDa) (r = 0,24, p = 0,04). In addition, a weak correlation between gelatinase activity of plasmatic 92 kDa MMP-9 and gelatinase of 180 kDa in SWS (r= 0,26 p = 0,03) was found, and a moderate correlation between plasmatic TIMP-2 and TIMP-2 of SWS (r = 0,32, p = 0,004).The results show that the gelatinase activity of SWS may reflect the concentrations of systemic inflammatory markers such as MMP-8 and MMP-9, also the concentration of TIMP-2 in the SWS may reflect the circulating concentration of TIMP-2. The evaluation of these results suggests that there is an attenuation of some inflammatory markers analyzed in the SWS and in plasma after treatment of PD. Furthermore, there are correlations between salivary and plasma levels in some of these markers. Because saliva sampling is less invasive, more studies about the correlations between these markers in these two fluids are necessary. Key words: saliva, plasma, matrix metalloproteinases, periodontal disease. LISTA DE ABREVIATURAS, SIGLAS E SÍMBOLOS BSA -

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Matrix metalloproteinase‐2 (MMP‐2) is present in the nucleus of cardiac myocytes and is capable of cleaving poly (ADP‐ribose) polymerase (PARP) in vitro

Cited by 237 publications

References 37 publications

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

Gelatinase-mediated migration and invasion of cancer cells

Concentrações de MMP-8, MMP-9, MPO, TIMP-1 e TIMP-2 na saliva e correlações com plasma

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