Tissue inhibitor of metalloproteinase-3 induces a Fas-associated death domain-dependent type II apoptotic pathway

被引:122
作者
Bond, M
Murphy, G
Bennett, MR
Newby, AC
Baker, AH
机构
[1] Univ Bristol, Bristol Royal Infirm, Bristol Heart Inst, Bristol BS2 8HW, Avon, England
[2] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England
[3] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England
[4] Univ Glasgow, Dept Med & Therapeut, Glasgow G11 6NT, Lanark, Scotland
关键词
D O I
10.1074/jbc.M111507200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tissue inhibitors of metalloproteinases (TIMPs) are important regulators of matrix metalloproteinase (MMP) and adamalysin metalloproteinase activity. We previously reported that overexpression of TIMP-3 inhibits MMPs and induces apoptotic cell death in a variety of cell types and demonstrated that apoptosis is mediated through the N terminus of TIMP-3, which harbors the MMP inhibitory domain. However, little is known about the mechanisms underlying TIMP-3-induced apoptosis. Here we demonstrate that overexpression of TIMP-3 induced activation of initiator caspase-8 and -9 and promoted caspase-mediated cleavage of the death substrates poly(ADP-ribose) polymerase and focal adhesion kinase. Furthermore, TIMP-3 induced mitochondrial activation as demonstrated by loss of mitochondrial membrane potential and release of cytochrome c. Intervention studies demonstrated that overexpression of Bcl-2, the anti-apoptotic mitochondrial membrane protein, or CrmA, a viral serpin inhibitor of caspase-8, completely inhibited TIMP-3-induced apoptosis. Furthermore, a dominant-negative Fas-associated death domain mutant inhibited TIMP-3-induced death substrate cleavage and apoptotic death. Taken together, these results indicate that TIMP-3 overexpression induces a type II apoptotic pathway initiated via a Fas-associated death domain-dependent mechanism.
引用
收藏
页码:13787 / 13795
页数:9
相关论文
共 61 条
  • [21] TISSUE INHIBITOR OF METALLOPROTEINASE-2 STIMULATES FIBROBLAST PROLIFERATION VIA A CAMP-DEPENDENT MECHANISM
    CORCORAN, ML
    STETLERSTEVENSON, WG
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (22) : 13453 - 13459
  • [22] SEQUENCE OF HUMAN-TISSUE INHIBITOR OF METALLOPROTEINASES AND ITS IDENTITY TO ERYTHROID-POTENTIATING ACTIVITY
    DOCHERTY, AJP
    LYONS, A
    SMITH, BJ
    WRIGHT, EM
    STEPHENS, PE
    HARRIS, TJR
    MURPHY, G
    REYNOLDS, JJ
    [J]. NATURE, 1985, 318 (6041) : 66 - 69
  • [23] Expression of tissue inhibitor of metalloproteinases-3 in human atheroma and regulation in lesion-associated cells - A potential protective mechanism in plaque stability
    Fabunmi, RP
    Sukhova, GK
    Sugiyama, S
    Libby, P
    [J]. CIRCULATION RESEARCH, 1998, 83 (03) : 270 - 278
  • [24] Accelerated apoptosis in the Timp-3-deficient mammary gland
    Fata, JE
    Leco, KJ
    Voura, EB
    Yu, HYE
    Waterhouse, P
    Murphy, G
    Moorehead, RA
    Khokha, R
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2001, 108 (06) : 831 - 841
  • [25] TIMP-1/MMP-9 imbalance in an EBV-immortalized B lymphocyte cellular model:: evidence for TIMP-1 multifunctional properties
    Gaudin, P
    Trocmé, C
    Berthier, S
    Kieffer, S
    Boutonnat, J
    Lamy, C
    Surla, A
    Garin, J
    Morel, F
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2000, 1499 (1-2): : 19 - 33
  • [26] GENG YJ, 1995, CIRCULATION, V92, P471
  • [27] Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3
    George, SJ
    Lloyd, CT
    Angelini, GD
    Newby, AC
    Baker, AH
    [J]. CIRCULATION, 2000, 101 (03) : 296 - 304
  • [28] HUMAN 72-KILODALTON TYPE-IV COLLAGENASE FORMS A COMPLEX WITH A TISSUE INHIBITOR OF METALLOPROTEASES DESIGNATED TIMP-2
    GOLDBERG, GI
    MARMER, BL
    GRANT, GA
    EISEN, AZ
    WILHELM, S
    HE, CS
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (21) : 8207 - 8211
  • [29] Gomez DE, 1997, EUR J CELL BIOL, V74, P111
  • [30] Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4
    Greene, J
    Wang, MS
    Liu, YLE
    Raymond, LA
    Rosen, C
    Shi, YNE
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (48) : 30375 - 30380