Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Spotlight Review
  • Published:

Review

Noncaspase proteases in apoptosis

Leukemia volume 14, pages 1695–1703 (2000)Cite this article

Abstract

Biochemical and genetic analysis of apoptosis has determined that intracellular proteases are key effectors of cell death pathways. In particular, early studies have pointed to the primacy of caspase proteases as mediators of execution. More recently, however, evidence has accumulated that noncaspases, including cathepsins, calpains, granzymes, and the proteasome complex, also have roles in mediating and promoting cell death. An important goal is to understand the importance of distinct noncaspases in various forms of apoptosis, and to determine whether pathways mediated by noncaspase proteases intersect with those mediated by caspases. In this review the roles of noncaspase proteases in the biochemistry of apoptosis will be discussed. Leukemia (2000) 14, 1695–1703.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR . The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme Cell 1993 75: 641–652

    Article  CAS  PubMed  Google Scholar 

  2. Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van Ness K, Greenstreet TA, March CJ, Kronheim SR, Druck T, Cannizzaro LA, Huebner K, Black RA . Molecular cloning of the interleukin-1β converting enzyme Science 1992 256: 97–100

    CAS  PubMed  Google Scholar 

  3. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Mokineaux SM, Weidner JR, Aunins J, Elliston KO, Ayala JM, Casano FJ, Chin J, Ding GJ-F, Egger LA, Gaffney EP, Limjuco G, Palyha OC, Raju SM, Rolando AM, Salley JP, Yamin T-T, Lee TD, Shively JE, MacCross M, Mumford RA, Schmidt JA, Tocci MJ . A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes Nature 1992 356: 768–774

    CAS  PubMed  Google Scholar 

  4. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J . Human ICE/CED-3 protease nomenclature Cell 1996 87: 171

    Article  CAS  PubMed  Google Scholar 

  5. Thornberry NA, Lazebnik Y . Caspases: enemies within Science 1998 281: 1312–1316

    CAS  PubMed  Google Scholar 

  6. Orlowski RZ . The role of the ubiquitin-proteasome pathway in apoptosis Cell Death Differ 1999 6: 303–313

    CAS  PubMed  Google Scholar 

  7. Schwartz MK . Tissue cathepsins as tumor markers Clin Chem Acta 1995 237: 67–78

    CAS  Google Scholar 

  8. Chapman HA, Riese RJ, Shi GP . Emerging roles for cysteine proteases in human biology Ann Rev Physiol 1997 59: 63–88

    CAS  Google Scholar 

  9. Westley B, Rochefort H . A secreted glycoprotein induced by estrogen in human breast cancer cell lines Cell 1980 20: 353–362

    CAS  PubMed  Google Scholar 

  10. Capony F, Rougeot C, Montcourrier P, Cavailles V, Salazar G, Rochefort H . Increased secretion, altered processing and glycosylation of procathepsin D in mammary cancer cells Cancer Res 1989 49: 3904–3909

    CAS  PubMed  Google Scholar 

  11. Erickson AH . Biosynthesis of lysosomal endopeptidases J Cell Biochem 1989 40: 31–41

    CAS  PubMed  Google Scholar 

  12. Fujita H, Tanaka Y, Noguchi Y, Kono A, Himeno M, Kato K . Isolation and sequencing of a cDNA clone encoding rat liver lysosomal cathepsin D and the structure of three forms of mature enzymes Biochem Biophys Res Commun 1991 179: 190–196

    CAS  PubMed  Google Scholar 

  13. Godbold GD, Ahn K, Yeyeodu S, Lee LF, Ting JP, Erickson AH . Biosynthesis and intracellular targeting of the lysosomal aspartic proteinase cathepsin D Adv Exp Med Biol 1998 436: 153–162

    CAS  PubMed  Google Scholar 

  14. Kornblau SM . The role of apoptosis in the pathogenesis, prognosis, and therapy of hematologic malignancies Leukemia 1998 12: (Suppl1) 41–46

    Google Scholar 

  15. Mort JS, Recklies AD . Interrelationship of active and latent secreted human cathepsin B precursors Biochem J 1986 233: 57–63

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sloane BF, Honn KV . Cysteine proteinases and metastasis Cancer Metast Rev 1984 3: 249–263

    CAS  Google Scholar 

  17. Briozzo P, Morisset M, Capony F, Rougeot C, Rochefort H . In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells Cancer Res 1988 48: 3688–3692

    CAS  PubMed  Google Scholar 

  18. Leto G, Gebbia N, Rausa L, Tumminello FM . Cathepsin D in the malignant progression of neoplastic disease Anticancer Res 1992 12: 235–240

    CAS  PubMed  Google Scholar 

  19. Mignatti P, Rifkin DB . Biology and biochemistry of proteinases in tumor invasion Physiol Rev 1993 73: 161–195

    CAS  PubMed  Google Scholar 

  20. Thorpe SM, Rochefort H, Garcia M, Freiss G, Christensen IJ, Khalaf S, Paolucci F, Pau B, Rasmussen BB, Rose C . Association between high concentration of 52-kDa cathepsin D and poor prognosis in primary human breast cancer Cancer Res 1989 49: 6008–6014

    CAS  PubMed  Google Scholar 

  21. Tandon AK, Clark GM, Chamness GC, Chirgwin JM, McGuire WL . Cathepsin D and prognosis in breast cancer New Engl J Med 1990 322: 297–302

    CAS  PubMed  Google Scholar 

  22. Kute TE, Shao ZM, Sugg NK, Long RT, Russell GB, Case D . Cathepsin D as a prognostic indicator of node-negative breastcancer patients using both immunoassays and enzymatic assays Cancer Res 1992 52: 198–203

    Google Scholar 

  23. Garcia M, Platet N, Liaudet E, Laurent V, Derocq D, Brouillet J-P, Rochefort H . Biological and clinical significance of cathepsin D in breast cancer metastasis Stem Cells 1996 14: 642–650

    CAS  PubMed  Google Scholar 

  24. English HF, Kyprianou N, Isaacs JT . Relationship between DNA fragmentation and apoptosis in programmed cell death in the rat prostate following castration Prostate 1989 15: 233–250

    CAS  PubMed  Google Scholar 

  25. Walker NI, Bennett RE, Kerr JF . Cell death by apoptosis during involution of the lactating breast in mice and rats Am J Anat 1989 185: 19–32

    CAS  PubMed  Google Scholar 

  26. Guenette RS, Mooibroek M, Wong K, Wong P, Tenniswood M . Cathepsin B, a cysteine protease implicated in metastatic progression, is also expressed during regression of the rat prostate and mammary glands Eur J Biochem 1994 226: 311–321

    CAS  PubMed  Google Scholar 

  27. Sensibar JA, Liu XX, Patai B, Alger B, Lee C . Characterization of castration-induced cell death in the rat prostate by immunohistochemical localization of cathepsin D Prostate 1990 16: 263–276

    CAS  PubMed  Google Scholar 

  28. Roberts LR, Kurosawa H, Bronk SF, Fesmier PJ, Agellon LB, Leung W-Y, Mao F, Gores GJ . Cathepsin B contributes to bile salt-induced apoptosis of rat hepatocytes Gastroenterology 1997 113: 1714–1726

    CAS  PubMed  Google Scholar 

  29. Roberts LR, Adjei PN, Gores GJ . Cathepsins as effector proteases in hepatocyte apoptosis Cell Biochem Biophys 1999 30: 71–88

    Article  CAS  PubMed  Google Scholar 

  30. Nishimura Y, Kawabata T, Kato K . Identification of latent cathepsins B and L in microsomal lumen: characterization of enzymatic activation and proteolytic processing in vitro Arch Biochem Biophys 1988 261: 64–71

    CAS  PubMed  Google Scholar 

  31. Rowan AD, Mason P, Mach L, Mort JS . Rat procathepsin B: Proteolytic processing to the mature form in vitro J Biol Chem 1992 267: 15993–15999

    CAS  PubMed  Google Scholar 

  32. Shibata M, Kanamori S, Isahara K, Ohsawa Y, Konishi A, Kametaka S, Watanabe T, Ebisu S, Ishido K, Kominami E, Uchiyama Y . Participation of cathepsins B and D in apoptosis of PC12 cells following serum deprivation Biochem Biophys Res Commun 1998 251: 199–203

    CAS  PubMed  Google Scholar 

  33. Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, Lippa C, Nixon RA . Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: evidence for early up-regulation of the endosomal-lysosomal system Neuron 1995 14: 671–680

    CAS  PubMed  Google Scholar 

  34. Isahara K, Ohsawa Y, Kanamori S, Shibata M, Waguri S, Sato N, Gotow T, Watanabe T, Momoi T, Urase K, Kominami E, Uchiyama Y . Regulation of a novel pathway for cell death by lysosomal aspartic and cysteine proteinases Neuroscience 1999 91: 233–249

    CAS  PubMed  Google Scholar 

  35. Lotem J, Sachs L . Control of apoptosis in hematopoiesis and leukemia by cytokines, tumor suppressor and oncogenes Leukemia 1996 10: 925–931

    CAS  PubMed  Google Scholar 

  36. Drexler HG, Zaborski M, Quentmeier H . Cytokine response profiles of human myeloid factor-dependent leukemia cell lines Leukemia 1997 11: 701–708

    CAS  PubMed  Google Scholar 

  37. Antoku K, Liu Z, Johnson DE . IL-3 withdrawal activates a CrmA-insensitive poly(ADP-ribose) polymerase cleavage enzyme in factor-dependent myeloid progenitor cells Leukemia 1998 12: 682–689

    CAS  PubMed  Google Scholar 

  38. Blalock WL, Weinstein-Oppenheimer C, Chang F, Hoyle PE, Wang XY, Algate PA, Franklin RA, Oberhaus SM, Steelman LS, McCubrey JA . Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs Leukemia 1999 13: 1109–1166

    CAS  PubMed  Google Scholar 

  39. Deiss LP, Galinka H, Berissi H, Cohen O, Kimchi A . Cathepsin D protease mediates programmed cell death induced by interferon-γ, Fas/APO-1 and TNF-α EMBO J 1996 15: 3861–3870

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wu GS, Saftig P, Peters C, El-Deiry WS . Potential role for cathepsin D in p53-dependent tumor suppression and chemosensitivity Oncogene 1998 16: 2177–2183

    CAS  PubMed  Google Scholar 

  41. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors Cell 1998 94: 481–490

    CAS  PubMed  Google Scholar 

  42. Li H, Zhu H, Xu C-J, Yuan J . Cleavage of BID by caspase 8 mediates the mitochondrial damage in Fas pathway of apoptosis Cell 1998 94: 491–501

    CAS  PubMed  Google Scholar 

  43. Friesen C, Fulda S, Debatin KM . Cytotoxic drugs and the CD95 pathway Leukemia 1999 13: 1854–1858

    CAS  PubMed  Google Scholar 

  44. Adams JM, Cory S . The Bcl-2 protein family: arbiters of cell survival Science 1998 281: 1322–1326

    CAS  PubMed  Google Scholar 

  45. Liu X, Zou H, Slaughter C, Wang X . DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis Cell 1997 89: 175–184

    Article  CAS  PubMed  Google Scholar 

  46. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S . A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD Nature 1998 391: 43–50

    CAS  PubMed  Google Scholar 

  47. Rowan S, Fisher DE . Mechanisms of apoptotic cell death Leukemia 1997 11: 457–465

    CAS  PubMed  Google Scholar 

  48. Wolf BB, Green DR . Suicidal tendencies: apoptotic cell death by caspase family proteinases J Biol Chem 1999 274: 20049–20052

    CAS  PubMed  Google Scholar 

  49. Brunk UT, Zhang H, Roberg K, Ollinger K . Lethal hydrogen peroxide toxicity involves lysosomal iron-catalyzed reactions with membrane damage Redox Rep 1995 1: 267–277

    CAS  PubMed  Google Scholar 

  50. Li W, Yuan XM, Olsson AG, Brunk UT . Uptake of oxidized LDL by macrophages results in partial lysosomal enzyme inactivation and relocation Arterioscler Thromb Vasc Biol 1998 18: 177–184

    CAS  PubMed  Google Scholar 

  51. Roberg K, Ollinger K . Oxidative stress causes relocation of the lysosomal enzyme cathepsin D with ensuing apoptosis in neonatal rat cardiomyocytes Am J Pathol 1998 152: 1151–1156

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Vancompernolle K, Van Herreweghe F, Pynaert G, Van de Craen M, De Vos K, Totty N, Sterling A, Fiers W, Vandenabeele P, Grooten J . Atractyloside-induced release of cathepsin B, a protease with caspase-processing activity FEBS Lett 1998 438: 150–158

    CAS  PubMed  Google Scholar 

  53. Zhou Q, Salvesen GS . Activation of pro-caspase-7 by serine proteases includes a non-canonical specificity Biochem J 1997 324: 361–364

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Schotte P, Declercq W, Van Huffel S, Vandenabeele P, Beyaert R . Non-specific effects of methyl ketone peptide inhibitors of caspases FEBS Lett 1999 442: 117–121

    CAS  PubMed  Google Scholar 

  55. Guroff G . A neutral, calcium-activated proteinase from the soluble fraction of rat brain J Biol Chem 1964 239: 149–155

    CAS  PubMed  Google Scholar 

  56. Mellgren RL . Canine cardiac calcium-dependent proteases: resolution of two forms with different requirements for calcium FEBS Lett 1980 109: 129–133

    CAS  PubMed  Google Scholar 

  57. Murachi T, Tanaka K, Hatanaka M, Murakami T . Intracellular Ca2+-dependent protease (calpain) and its high-molecular-weight endogenous inhibitor (calpastatin) Adv Enzyme Reg 1981 19: 407–424

    CAS  Google Scholar 

  58. Sorimachi H, Saido TC, Suzuki K . New era of calpain research: discovery of tissue-specific calpains FEBS Lett 1994 341: 1–5

    Google Scholar 

  59. Carfoli E, Molinari M . Calpain: a protease in search of a function? Biochem Biophys Res Commun 1998 247: 193–203

    Google Scholar 

  60. Sorimachi H, Ishiura S, Suzuki K . A novel tissue-specific calpain species expressed predominantly in the stomach comprises two alternative splicing products with and without Ca(2+)-binding domain J Biol Chem 1993 268: 19476–19482

    CAS  PubMed  Google Scholar 

  61. Sorimachi H, Toyama-Sorimachi N, Saido TC, Kawasaki H, Sugita H, Miyasaka M, Arahata K, Ishiura S, Suzuki K . Muscle-specific calpain, p94, is degraded by autolysis immediately after translation, resulting in disappearance from muscle J Biol Chem 1993 268: 10593–10605

    CAS  PubMed  Google Scholar 

  62. Wilson R, Ainscough R, Anderson K, Baynes C, Berks M, Bonfield J, Burton J, Connell M, Copsey T, Cooper J, Coulson A, Craxton M, Dear S, Du Z, Durbin R, Favello A, Fraser A, Fulton L, Gardner A, Green P, Hawkins T, Hillier L, Jler M, Johnston L, Jones M, Kershaw J, Kirsten J, Laisster N, Latreille P, Lightning J, Lloyd C, Mortimore B, O’Callaghan M, Parsons J, Percy C, Rifken L, Roopra A, Saunders D, Shownkeen R, Sims M, Smaldon N, Smith A, Smith M, Sonnhammer E, Staden R, Sulston J, Thierry-Mieg J, Thomas K, Vaudin M, Vaughan K, Waterston R, Watson A, Weinstock L, Wilkinson-Sproat J, Wohldman P . 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans Nature 1994 368: 32–38

    CAS  PubMed  Google Scholar 

  63. Sasaki T, Yoshimura N, Kikuchi T, Hatanaka M, Kitahara A, Sakihama T, Murachi T . Similarity and dissimilarity in subunit structures of calpains I and II from various sources as demonstrated by immunological cross-reactivity J Biochem 1983 94: 2055–2061

    CAS  PubMed  Google Scholar 

  64. Murachi T . Intracellular regulatory system involving calpain and calpastatin Biochem Int 1989 18: 263–294

    CAS  PubMed  Google Scholar 

  65. Croall DE, DeMartino GN . Calcium-activated neutral protease (calpain) system: Structure, function, and regulation Physiol Rev 1991 71: 813–847

    CAS  PubMed  Google Scholar 

  66. Blanchard H, Grochulski P, Li Y, Arthur JS, Davies PL, Elce JS, Cygler M . Structure of a calpain Ca(2+)-binding domain reveals a novel EF-hand and Ca(2+)-induced conformational changes Nature Struct Biol 1997 4: 532–538

    CAS  PubMed  Google Scholar 

  67. Molinari M, Anagli J, Carafoli E . Ca(2+)-activated neutral protease is active in the erythrocyte membrane in its nonautolyzed 80-kDa form J Biol Chem 1994 269: 27992–27995

    CAS  PubMed  Google Scholar 

  68. Suzuki K, Tsuji S, Ishiura S, Kimura Y, Kubota S, Imahori K . Autolysis of calcium-activated neutral protease of chicken skeletal muscle J Biochem 1981 90: 1787–1793

    CAS  PubMed  Google Scholar 

  69. Mellgren RL, Repetti A, Muck TC, Easly J . Rabbit skeletal muscle calcium-dependent protease requiring millimolar CA2+. Purification, subunit structure, and Ca2+-dependent autoproteolysis J Biol Chem 1982 257: 7203–7209

    CAS  PubMed  Google Scholar 

  70. DeMartino GN, Huff CA, Croall DE . Autoproteolysis of the small subunit of calcium-dependent protease II activates and regulates protease activity J Biol Chem 1986 261: 12047–12052

    CAS  PubMed  Google Scholar 

  71. Imajoh S, Kawasaki H, Suzuki K . Limited autolysis of calcium-activated neutral protease (CANP): reduction of the Ca2+-requirement is due to the NH2-terminal processing of the large subunit J Biochem 1986 100: 633–642

    CAS  PubMed  Google Scholar 

  72. Inomata M, Kasai Y, Nakamura M, Kawashima S . Activation mechanism of calcium-activated neutral protease. Evidence for the existence of intramolecular and intermolecular autolyses J Biol Chem 1988 263: 19783–19787

    CAS  PubMed  Google Scholar 

  73. Elce JS, Hegadorn C, Arthur JSC . Autolysis, Ca2+ requirement, and heterodimer stability in m-calpain J Biol Chem 1997 272: 11268–11275

    CAS  PubMed  Google Scholar 

  74. Waxman L, Krebs EG . Identification of two protease inhibitors from bovine cardiac muscle J Biol Chem 1978 253: 5888–5891

    CAS  PubMed  Google Scholar 

  75. Emori Y, Kawasaki H, Imajoh S, Imahori K, Suzuki K . Endogenous inhibitor for calcium-dependent cysteine protease contains four internal repeats that could be responsible for its multiple reactive sites Proc Natl Acad Sci USA 1987 84: 3590–3594

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Squier MKT, Miller ACK, Malkinson AM, Cohen JJ . Calpain activation in apoptosis J Cell Physiol 1994 159: 229–237

    CAS  PubMed  Google Scholar 

  77. Knepper-Nicolai B, Savill J, Brown SB . Constitutive apoptosis in human neutrophils requires synergy between calpains and the proteosome downstream of caspases J Biol Chem 1998 273: 30530–30536

    CAS  PubMed  Google Scholar 

  78. Waterhouse NJ, Finucane DM, Green DR, Elce JS, Kumar S, Alnemri ES, Litwack G, Khanna KK, Lavin MF, Watters DJ . Calpain activation is upstream of caspases in radiation-induced apoptosis Cell Death Differ 1998 5: 1051–1061

    CAS  PubMed  Google Scholar 

  79. Wood DE, Newcomb EW . Caspase-dependent activation of calpain during drug-induced apoptosis J Biol Chem 1999 274: 8309–8315

    CAS  PubMed  Google Scholar 

  80. Xie H, Johnson GV . Ceramide selectively decreases tau levels in differentiated PC12 cells through modulation of calpain I J Neurochem 1997 69: 1020–1030

    CAS  PubMed  Google Scholar 

  81. Debiasi RL, Squier MKT, Pike B, Wynes M, Dermody TS, Cohen JJ, Tyler KL . Reovirus-induced apoptosis is preceded by increased cellular calpain activity and is blocked by calpain inhibitors J Virol 1999 73: 695–701

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kohli V, Madden JF, Bentley RC, Clavien P-A . Calpain mediates ishemic injury of the liver through modulation of apoptosis and necrosis Gastroenterol 1999 116: 168–178

    CAS  Google Scholar 

  83. Saito K, Elce JS, Hamos JE, Nixon RA . Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration Proc Natl Acad Sci USA 1993 90: 2628–2632

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Nixon RA, Saito K-I, Grynspan F, Griffin WR, Katayama S, Honda T, Mohan PS, Shea TB, Beermann M . Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer’s disease Ann NY Acad Sci 1994 747: 77–91

    CAS  PubMed  Google Scholar 

  85. Mouatt-Prigent A, Karlsson JO, Agid Y, Hirsch EC . Increased M-calpain expression in the mesencephalon of patients with Parkinson's disease but not in other neurodegenerative disorders involving the mesencephalon: a role in nerve cell death? Neurosci 1996 73: 979–987

    CAS  Google Scholar 

  86. Aoyagi T, Takeuchi T, Matsuzaki A, Kawamura K, Kondo S . Leupeptins, new protease inhibitors from Actinomycetes J Antibiotics 1969 22: 283–286

    CAS  Google Scholar 

  87. Barrett AJ, Kembhavi AA, Hanada K . E-64 [L-trans-epoxysuccinyl-leucyl-amido(4-guanidino)butane] and related epoxides as inhibitors of cysteine proteinases Acta Biol Med Germ 1981 40: 1513–1517

    CAS  PubMed  Google Scholar 

  88. Wang KK . Developing selective inhibitors of calpain Trends Pharm Sci 1990 11: 139–142

    CAS  PubMed  Google Scholar 

  89. Mehdi S . Cell-penetrating inhibitors of calpain Trends Biochem Sci 1991 16: 150–153

    CAS  PubMed  Google Scholar 

  90. Tsujinaka T, Kajiwara Y, Kambayashi J, Sakon M, Higuchi N, Tanaka T, Mori T . Synthesis of a new cell penetrating inhibitor (calpeptin) Biochem Biophys Res Commun 1988 153: 1201–1208

    CAS  PubMed  Google Scholar 

  91. Wang KK, Nath R, Posner A, Raser KJ, Buroker-Kilgore M, Hajimohammadreza I, Probert W, Marcoux FW, Ye Q, Takano E, Hatanaka M, Maki M, Caner H, Collins JL, Fergus A, Lee KS, Lunney EA, Hays SJ, Yuen P . An alpha-mercaptoacrylic acid derivative is a selective non-peptide cell-permeable calpain inhibitor and is neuroprotective Proc Natl Acad Sci USA 1996 93: 6687–6692

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Squier MKT, Cohen JJ . Calpain, an upstream regulator of thymocyte apoptosis J Immunol 1997 158: 3690–3697

    CAS  PubMed  Google Scholar 

  93. Squier MKT, Sehnert AJ, Sellins KS, Malkinson AM, Takano E, Cohen JJ . Calpain and calpastatin regulate neutrophil apoptosis J Cell Physiol 1999 178: 311–319

    CAS  PubMed  Google Scholar 

  94. Vanags DM, Porn-Ares I, Coppola S, Burgess DH, Orrenius S . Protease involvement in fodrin cleavage and phosphatidylserine exposure in apoptosis J Biol Chem 1996 271: 31075–31085

    CAS  PubMed  Google Scholar 

  95. Spinedi A, Oliverio S, Di Sano F, Piacentini M . Calpain involvement in calphostin C-induced apoptosis Biochem Pharm 1998 56: 1489–1492

    CAS  PubMed  Google Scholar 

  96. Wolf BB, Goldstein JC, Stennicke HR, Beere H, Amarante-Mendes GP, Salvesen GS, Green DR . Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activation Blood 1999 94: 1683–1692

    CAS  PubMed  Google Scholar 

  97. Gressner AM, Lahme B, Roth S . Attenuation of TGF-beta-induced apoptosis in primary cultures of hepatocytes by calpain inhibitors Biochem Biophys Res Commun 1997 231: 457–462

    CAS  PubMed  Google Scholar 

  98. Villa PG, Henzel WJ, Sensenbrenner M, Henderson CE, Pettmann B . Calpain inhibitors, but not caspase inhibitors, prevent actin proteolysis and DNA fragmentation during apoptosis J Cell Sci 1998 111: 713–722

    CAS  PubMed  Google Scholar 

  99. Jordan J, Galindo MF, Miller RJ . Role of calpain- and interleukin-1β converting enzyme-like proteases in the β-amyloid-induced death of rat hippocampal neurons in culture J Neurochem 1997 68: 1612–1621

    CAS  PubMed  Google Scholar 

  100. Yuan Y, Dopheide SM, Ivanidis C, Salem HH, Jackson SP . Calpain regulation of cytoskeletal signaling complexes in von Willebrand factor-stimulated platelets. Distinct roles for glycoprotein Ib-V-IX and glycoprotein IIb-IIIa (integrin alphaIIbbeta3) in von Willebrand factor-induced signal transduction J Biol Chem 1997 272: 21847–21854

    CAS  PubMed  Google Scholar 

  101. Martin SJ, O’Brien GA, Nishioka WK, McGahon AJ, Mahboubi A, Saido TC, Green DR . Proteolysis of fodrin (non-erythroid spectrin) during apoptosis J Biol Chem 1995 270: 6425–6428

    CAS  PubMed  Google Scholar 

  102. Cooray P, Yuan Y, Schoenwaelder SM, Mitchell CA, Salem HH, Jackson SP . Focal adhesion kinase (pp125FAK) cleavage and regulation by calpain Biochem J 1996 318: 41–47

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Meredith J Jr, Mu Z, Saido T, Du X . Cleavage of the cytoplasmic domain of integrin β3 subunit during endothelial cell apoptosis J Biol Chem 1998 273: 19525–19531

    PubMed  Google Scholar 

  104. Kishimoto A, Mikawa K, Hashimotos K, Yasuda I, Tanaka S, Tominaga MT, Kuroda T, Nishizuka Y . Limited proteolysis of protein kinase C subspecies by calcium-dependent neutral protease (calpain) J Biol Chem 1989 264: 4088–4092

    CAS  PubMed  Google Scholar 

  105. McGinnis KM, Whitton MM, Gnegy ME, Wang KKW . Calcium/calmodulin-dependent protein kinase IV is cleaved by caspase-3 and calpain in SH-SY5Y human neuroblastoma cells undergoing apoptosis J Biol Chem 1998 273: 19993–20000

    CAS  PubMed  Google Scholar 

  106. Watanabe N, Vande Woude GF, Ikawa Y, Sagata N . Specific proteolysis of the c-mos proto-oncogene product by calpain on fertilization of Xenopus eggs Nature 1989 342: 505–511

    CAS  PubMed  Google Scholar 

  107. Hirai S, Kawasaki H, Yaniv M, Suzuki K . Degradation of transcription factors, c-Jun and c-Fos, by calpain FEBS Lett 1991 287: 57–61

    CAS  PubMed  Google Scholar 

  108. Watt F, Molloy PL . Specific cleavage of transcription factors by the thiol protease, m-calpain Nucleic Acids Res 1993 21: 5092–5100

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Choi YH, Lee SJ, Nguyen P, Jang JS, Lee J, Wu ML, Takano E, Maki M, Henkart PA, Trepel JB . Regulation of cyclin D1 by calpain protease J Biol Chem 1997 272: 28479–28484

    CAS  PubMed  Google Scholar 

  110. Kubbutat MHG, Vousden KH . Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability Mol Cell Biol 1997 17: 460–468

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Wood DE, Thomas A, Devi LA, Berman Y, Beavis RC, Reed JC, Newcomb EW . Bax cleavage is mediated by calpain during drug-induced apoptosis Oncogene 1998 17: 1069–1078

    CAS  PubMed  Google Scholar 

  112. Porn-Ares MI, Samali A, Orrenius S . Cleavage of the calpain inhibitor, calpastatin, during apoptosis Cell Death Differ 1998 5: 1028–1033

    CAS  PubMed  Google Scholar 

  113. Wang KKW, Posmantur R, Nadimpalli R, Nath R, Mohan P, Nixon RA, Talanian RV, Keegan M, Herzog L, Allen H . Caspase-mediated fragmentation of calpain inhibitor protein calpastatin during apoptosis Arch Biochem Biophys 1998 356: 187–196

    CAS  PubMed  Google Scholar 

  114. Berke G . The CTL’s kiss of death Cell 1995 81: 9–12

    CAS  PubMed  Google Scholar 

  115. Kagi D, Lederman B, Burki K, Zinkernagel RM, Hengartner H . Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo Ann Rev Immunol 1996 14: 207–232

    CAS  Google Scholar 

  116. Nagata S, Golstein P . The Fas death factor Science 1995 267: 1449–1456

    CAS  PubMed  Google Scholar 

  117. Ashkenazi A, Dixit VM . Death receptors: signaling and modulation Science 1998 281: 1305–1308

    CAS  PubMed  Google Scholar 

  118. Doherty PC . Cell-mediated cytotoxicity Cell 1993 75: 607–612

    CAS  PubMed  Google Scholar 

  119. Shresta S, MacIvor DM, Heusel JW, Russell JH, Ley TJ . Natural killer and lymphokine-activated killer cells require granzyme B for the rapid induction of apoptosis in susceptible target cells Proc Natl Acad Sci USA 1995 92: 5679–5683

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Shresta S, Heusel JW, Macivor DM, Wesselschmidt RL, Russell JH, Ley TJ . Granzyme B plays a critical role in cytotoxic lymphocyte-induced apoptosis Immunol Rev 1995 146: 211–221

    CAS  PubMed  Google Scholar 

  121. Masson D, Tschopp J . Isolation of a lytic pore-forming protein (perforin) from cytolytic T lymphocytes J Biol Chem 1985 260: 9069–9072

    CAS  PubMed  Google Scholar 

  122. Young JD-E, Hengartner H, Podack ER, Cohn ZA . Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity Cell 1986 44: 849–859

    CAS  PubMed  Google Scholar 

  123. Tschopp J, Schafer S, Masson D, Peitsch MC, Heusser C . Phosphorylcholine acts as a calcium dependent receptor molecule for lymphocyte perforin Nature 1989 337: 272–274

    CAS  PubMed  Google Scholar 

  124. Smyth MJ, O’Connor MD, Trapani JA . Granzymes: A variety of serine protease specificities encoded by genetically distinct subfamilies J Leuk Biol 1996 60: 555–562

    CAS  Google Scholar 

  125. Zunino SJ, Bleackley RC, Martinez J, Hudig D . RNKP-1, a novel natural killer cell-associated serine protease gene cloned from RNK-16 cytotoxic lymphocytes J Immunol 1990 144: 2001–2009

    CAS  PubMed  Google Scholar 

  126. Lobe CG, Havele C, Bleackley RC . Cloning of two genes that are specifically expressed in activated cytotoxic T lymphocytes Proc Natl Acad Sci USA 1986 83: 1448–1452

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Odake S, Kam CM, Narasimhan L, Poe M, Blake JT, Krahenbuhl O, Tschopp J, Powers JC . Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins Biochem 1991 30: 2217–2227

    CAS  Google Scholar 

  128. Poe M, Blake JT, Boulton DA, Gammon M, Sigal NH, Wu JK, Zweerink HJ . Human cytotoxic lymphocyte granzyme B: its purification from granules and the characterization of substrate and inhibitor specificity J Biol Chem 1991 266: 98–103

    CAS  PubMed  Google Scholar 

  129. Shi L, Kraut RP, Aebersold R, Greenberg AH . A natural killer cell granule protein that induces DNA fragmentation and apoptosis J Exp Med 1992 175: 553–566

    CAS  PubMed  Google Scholar 

  130. Heusel JW, Wesselschmidt RL, Shresta S, Russell JH, Ley TJ . Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells Cell 1994 76: 977–987

    CAS  PubMed  Google Scholar 

  131. Froelich CJ, Orth K, Turbov J, Seth P, Gottlieb R, Babior B, Shah GM, Bleackley RC, Dixit VM, Hanna W . New paradigm for lymphocyte granule-mediated cytotoxicity. Target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis J Biol Chem 1996 271: 29073–29079

    CAS  PubMed  Google Scholar 

  132. Jans DA, Jans P, Briggs LJ, Sutton V, Trapani JA . Nuclear transport of granzyme B (fragmentin-2) J Biol Chem 1996 271: 30781–30789

    CAS  PubMed  Google Scholar 

  133. Shi L, Mai S, Israels S, Browne K, Trapani JA, Greenberg AH . Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization J Exp Med 1997 185: 853–866

    Google Scholar 

  134. Pinkoski MJ, Hobman M, Heibein JA, Tomaselli K, Li F, Seth P, Froelich CJ, Bleackley RC . Entry and trafficking of granzyme B in target cells during granzyme B-perforin-mediated apoptosis Blood 1998 92: 1044–1054

    CAS  PubMed  Google Scholar 

  135. Pinkoski MJ, Heibein JA, Barry M, Bleackley RC . Nuclear translocation of granzyme B in target cell apoptosis Cell Death Differ 2000 7: 17–24

    CAS  PubMed  Google Scholar 

  136. Pinkoski MJ, Winkler U, Hudig D, Bleackley RC . Binding of granzyme B in the nucleus of target cells. Recognition of an 80-kilodalton protein J Biol Chem 1996 271: 10225–10229

    CAS  PubMed  Google Scholar 

  137. Trapani JA, Browne KA, Smyth MJ, Jans DA . Localization of granzyme B in the nucleus. A putative role in the mechanism of cytotoxic lymphocyte-mediated apoptosis J Biol Chem 1996 271: 4127–4133

    CAS  PubMed  Google Scholar 

  138. Darmon AJ, Nicholson DW, Bleackley RC . Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B Nature 1995 377: 446–448

    CAS  PubMed  Google Scholar 

  139. Darmon AJ, Ley TJ, Nicholson DW, Bleackley RC . Cleavage of CPP32 by granzyme B represents a critical role for granzyme B in the induction of target cell DNA fragmentation J Biol Chem 1996 271: 21709–21712

    CAS  PubMed  Google Scholar 

  140. Martin SJ, Amarante-Mendes GP, Shi LF, Chuang TH, Casiano CA, O’Brien GA, Fitzgerald P, Tan EM, Bokoch GM, Greenberg AH, Green DR . The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism EMBO J 1996 15: 2407–2416

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Quan LT, Tewari M, O’Rourke K, Dixit VM, Snipas SJ, Poirier GG, Ray C, Pickup DJ, Salvesen GS . Proteolytic activation of the cell death protease Yama/CPP32 by granzyme B Proc Natl Acad Sci USA 1996 93: 1972–1976

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Fernandes-Alnemri T, Litwack G, Alnemri ES . Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family Cancer Res 1995 55: 2737–2742

    CAS  PubMed  Google Scholar 

  143. Orth K, Chinnaiyan AM, Garg M, Froelich CJ, Dixit VM . The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A J Biol Chem 1996 271: 16443–16446

    CAS  PubMed  Google Scholar 

  144. Fernandes-Alnemri T, Takahashi A, Armstrong R, Krebs J, Fritz L, Tomaselli KJ, Wang L, Yu Z, Croce CM, Salvesen G, Earnshaw WC, Litwack G, Alnemri ES . Mch3, a novel human apoptotic cysteine protease highly related to CPP32 Cancer Res 1995 55: 6045–6052

    CAS  PubMed  Google Scholar 

  145. Chinnnaiyan AM, Orth K, Hanna WL, Duan HJ, Poirier GG, Froelich CJ, Dixit VM . Cytotoxic T cell-derived granzyme B activates the apoptotic protease ICE-LAP3 Curr Biol 1996 6: 897–899

    Google Scholar 

  146. Gu Y, Sarnecki C, Fleming MA, Lippke JA, Bleackley RC, Su MS-S . Processing and activation of CMH-1 by granzyme B J Biol Chem 1996 271: 10816–10820

    CAS  PubMed  Google Scholar 

  147. Boldin MP, Goncharov TM, Goltsev YV, Wallach D . Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death Cell 1996 85: 803–815

    CAS  PubMed  Google Scholar 

  148. Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM . FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex Cell 1996 85: 817–827

    CAS  PubMed  Google Scholar 

  149. Duan H, Orth K, Chinnaiyan AM, Poirier GG, Froelich CJ, He W-W, Dixit VM . ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the cytotoxic T cell protease granzyme B J Biol Chem 1996 271: 16720–16724

    CAS  PubMed  Google Scholar 

  150. Fernandes-Alnemri T, Armstrong RC, Krebs J, Srinivasula SM, Wang L, Bullrich F, Fritz LC, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES . In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains Proc Natl Acad Sci USA 1996 93: 7464–7469

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Medema JP, Toes REM, Scaffidi C, Zheng TS, Flavell RA, Melief CJM, Peter ME, Offringa R, Krammer PH . Cleavage of FLICE (caspase-8) by granzyme B during cytotoxic T lymphocyte-induced apoptosis Eur J Immunol 1997 27: 3492–3498

    CAS  PubMed  Google Scholar 

  152. Van de Craen M, Van den brande I, Declercq W, Irmler M, Beyaert R, Tschopp J, Fiers W, Vandenabeele P . Cleavage of caspase family members by granzyme B: a comparative study in vitro Eur J Immunol 1997 27: 1296–1299

    CAS  PubMed  Google Scholar 

  153. Talanian RV, Yang XH, Turbov J, Seth P, Ghayur T, Casiano CA, Orth K, Froelich CJ . Granule-mediated killing: pathways for granzyme B-initiated apoptosis J Exp Med 1997 186: 1323–1331

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Shi L, Chen G, MacDonald G, Bergeron L, Li H, Miura M, Rotello RJ, Miller DK, Li P, Seshadri T, Yuan J, Greenberg AH . Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B Proc Natl Acad Sci USA 1996 93: 11002–11007

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Andrade F, Roy S, Nicholson D, Thornberry N, Rosen A, Casciola-Rosen L . Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis Immunity 1998 8: 451–460

    CAS  PubMed  Google Scholar 

  156. Gershenfeld HK, Weissman IL . Cloning of a cDNA for a T cell-specific serine protease from a cytotoxic T lymphocyte Science 1986 232: 854–858

    CAS  PubMed  Google Scholar 

  157. Masson D, Zamai M, Tschopp J . Identification of granzyme A isolated from cytotoxic T-lymphocyte-granules as one of the proteases encoded by CTL-specific genes FEBS Lett 1986 208: 84–88

    CAS  PubMed  Google Scholar 

  158. Ebnet K, Hausmann M, Lehmann-Grube F, Mullbacher A, Kopf M, Lamers M, Simon MM . Granzyme A-deficient mice retain potent cell-mediated cytotoxicity EMBO J 1995 14: 4230–4239

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Mullbacher A, Ebnet K, Blanden RV, Hla RT, Stehle T, Museteanu C, Simon MM . Granzyme A is critical for recovery of mice from infection with the natural cytopathic viral pathogen, ectromelia Proc Natl Acad Sci USA 1996 93: 5783–5787

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Shresta S, Graubert TA, Thomas DA, Raptis SZ, Ley TJ . Granzyme A initiates an alternative pathway for granule-mediated apoptosis Immunity 1999 10: 595–605

    CAS  PubMed  Google Scholar 

  161. Hayes MP, Berrebi GA, Henkart PA . Induction of target cell DNA release by the cytotoxic T lymphocyte granule protease granzyme A J Exp Med 1989 170: 933–946

    CAS  PubMed  Google Scholar 

  162. Beresford PJ, Xia Z, Greenberg AH, Lieberman J . Granzyme A loading induces rapid cytolysis and a novel form of DNA damage independently of caspase activation Immunity 1999 10: 585–594

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medicine and Pharmacology, University of Pittsburgh, and the University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    DE Johnson

Authors
  1. DE Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johnson, D. Noncaspase proteases in apoptosis. Leukemia 14, 1695–1703 (2000). https://doi.org/10.1038/sj.leu.2401879

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401879

Keywords

This article is cited by

Search

Advanced search

Quick links