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.

  • Review
  • Published:

Caspase-independent cell death?

Oncogene volume 23, pages 2766–2773 (2004)Cite this article

Abstract

Many cells die with apoptotic morphology and with documented activation of an effector caspase, but there are also many exceptions. Cells frequently display activation of other proteases, including granzymes, lysosomal cathepsins, matrix metalloproteinases, and proteasomal proteases, and others display morphologies that are not fully consistent with classical apoptosis. In some experimental situations, evidence of caspase-dependent death is indirect, demonstrating that the cell can activate caspases rather than that it does. In other situations, such as involution of mammary or prostate tissue, many cells display autophagic or other morphology different from apoptosis, and there is considerable evidence for the activation of a lysosomal system. Prior to total collapse and necrosis, cells that are in trouble can activate numerous physiological pathways toward self-destruction. Intrinsic or extrinsic routes to effector caspase activation are frequently the most rapid and efficient. If neither of these routes is immediately available, owing to mutation, genetic manipulation, inhibitor, or the biology of the cell, other routes may be followed, leading to variant forms of cell death that may display one or more characteristics of apoptosis. Experimental and therapeutic procedures must account for this possibility.

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

Figure 2
Figure 1

Similar content being viewed by others

References

  • Allombert-Blaise C, Tamiji S, Mortier L, Fauvel H, Tual M, Delaporte E, Piette F, DeLassale EM, Formstecher P, Marchetti P and Polakowska R . (2003). Cell Death Differ., 10, 850–852.

  • Andersson M, Honarvar A, Sjostrand J, Peterson A and Karlsson JO . (2003). Exp. Eye Res., 76, 175–182.

  • Arama E, Agapite J and Steller H . (2003). Dev. Cell, 4, 687–697.

  • Baehrecke EH . (2003). Dev. Cell, 4, 608–609.

  • Bauvy C, Gane P, Arico S, Codogno P and Ogier-Denis E . (2001). Exp. Cell Res., 268, 139–149.

  • Berg CP, Engels IH, Rothbart A, Lauber K, Renz A, Schlosser SF, Schulze-Osthoff K and Wesselborg S . (2001). Cell Death Differ., 8, 1197–1206.

  • Bolognia JL . (1995). Am. J. Med., 98 (Suppl 1A), 99S–103S.

  • Bowen ID, Morgan SM and Mullarkey K . (1993). Cell Biol. Int. Rep., 17, 13–34.

  • Boya P, Andreau K, Poncet D, Zamzami N, Perfettini JL, Metivier D, Ojcius DM, Jaattela M and Kroemer G . (2003). J. Exp. Med., 197, 1323–1334.

  • Bratosin D, Estaquier J, Petit F, Arnoult D, Quatannens B, Tissier JP, Slomianny C, Sartiaux C, Alonso C, Huart JJ, Montreuil J and Ameisen JC . (2001b). Cell Death Differ., 8, 1143–1156.

  • Bratosin D, Estaquier J, Petit F, Arnoult D, Quatannens B, Tissier JP, Slomianny C, Sartiaux C, Alonso C, Huart JJ, Montreuil J and Ameisen JC . (2001a). Cell Death Differ., 8, 1143–1156.

  • Cakouros D, Daish T, Martin D, Baehrecke EH and Kumar S . (2002). J. Cell Biol., 157, 985–995.

  • Cerri PS, Boabaid F and Katchburian E . (2003). J. Periodontal Res., 38, 223–226.

  • Chua CC, Chua BH, Chen Z, Landy C and Hamdy RC . (2003). Biochim. Biophys. Acta, 1642, 79–85.

  • Clarke PGH . (1990). Anat. Embryol., 181, 195–213.

  • Clarke PGH and Clarke S . (1996). Anat. Embryol., 193, 81–99.

  • Cotman CW, Cribbs DH, Pike CJ and Ivins KJ . (1998). When Cells Die: A Comprehensive Evaluation of Apoptosis and Programmed Cell Death, Lockshin RA, Zakeri Z and Tilly JL (eds). Wiley-Liss: New York, pp. 385–410.

    Google Scholar 

  • Counis MF, Chaudun E, Arruti C, Oliver L, Sanwal M, Courtois Y and Torriglia A . (1998). Cell Death Differ., 5, 251–261.

  • Dahm R . (1999). Ophthalmic Res., 31, 163–183.

  • Dahm R, Gribbon C, Quinlan RA and Prescott AR . (1997). Biochem. Soc. Trans., 25, S584.

  • Dahm R and Prescott AR . (2002). Ophthalmic Res., 34, 288–294.

  • Daugas E, Cande C and Kroemer G . (2001). Cell Death Differ., 8, 1131–1133.

  • Dorstyn L, Colussi PA, Quinn LM, Richardson H and Kumar S . (1999). Proc. Natl. Acad. Sci. USA, 96, 4307–4312.

  • Dorstyn L, Read SH, Quinn LM, Richardson H and Kumar S . (1999). J. Biol. Chem., 274, 30778–30783.

  • Elmore SP, Qian T, Grissom SF and Lemasters JJ . (2001). FASEB J., 15, 2286–2287.

  • Fromm L and Overbeek PA . (1997). Dev. Genet., 20, 276–287.

  • Gandarillas A, Goldsmith LA, Gschmeissner S, Leigh IM and Watt FM . (1999). Exp. Dermatol., 8, 71–79.

  • Gao CY, Zakeri Z, Zhu Y, He H and Zelenka PS . (1997). Dev. Genet., 20, 267–275.

  • Gniadecki R, Olszewska H and Gajkowska B . (2001). Exp. Dermatol., 10, 71–79.

  • Gorski SM, Chittaranjan S, Pleasance ED, Freeman JD, Anderson CL, Varhol RJ, Coughlin SM, Zuyderduyn SD, Jones SJ and Marra MA . (2003). Curr. Biol, 13, 358–363.

  • Haas AL, Baboshina O, Williams B and Schwartz LM . (1995). J. Biol. Chem., 270, 9407–9412.

  • Halaby R, Zakeri Z and Lockshin RA . (1994). Biochem. Cell Biol., 72, 597–601.

  • Harvey NL, Daish T, Mills K, Dorstyn L, Quinn LM, Read SH, Richardson H and Kumar S . (2001). J. Biol. Chem., 276, 25342–25350.

  • Helminen HJ, Ericsson JL and Orrenius S . (1968). J. Ultrastruct. Res., 25, 240–252.

  • Hensey C and Gautier J . (1999). Mechanisms of Cell Death, Zakeri Z, Lockshin RA, and Benitez-Bribiesca L (eds). New York Academy of Sciences: New York City, pp. 105–119.

    Google Scholar 

  • Horvitz HR, Shaham S and Hengartner MO . (1994). Cold Spring Harbor Symp. Quant. Biol., 59, 377–386.

  • Horvitz HR, Sternberg PW, Greenwald IS, Fixsen W and Ellis HM . (1983). Cold Spring Harbor Symp. Quant. Biol., 48 (Part 2), 453–463.

  • Ishizaki Y, Jacobson MD and Raff MC . (1998). J. Cell Biol., 140, 153–158.

  • Jäättelä M and Tschopp J . (2003). Nat. Immunol., 4, 416–423.

  • Jellinger KA and Stadelmann C . (2001). J. Alzheimers Dis., 3, 31–40.

  • Jochová J, Quaglino D, Zakeri Z, Woo K, Sikorska M, Weaver VM and Lockshin RA . (1997a). Dev. Genet., 21, 249–257.

  • Jochová J, Zakeri Z and Lockshin RA . (1997b). Cell Death Differ., 4, 140–149.

  • Kane DJ, Örd T, Anton R and Bredesen DE . (1995). J.Neurosci. Res., 40, 269–275.

  • Kerr JFR . (1971). J. Pathol., 105, 13–20.

  • Kerr JFR, Harmon BV and Searle JW . (1974). J. Cell Sci., 14, 571–585.

  • Kerr JFR, Wyllie AH and Currie AR . (1972). Br. J. Cancer, 26, 239–257.

  • Kierszenbaum AL . (2001). Mol. Reprod. Dev., 58, 1–3.

  • Knudson CM, Tung KSK, Tourtellotte WG, Brown GAJ and Korsmeyer SJ . (1995). Science, 270, 96–99.

  • Kroemer G, Dallaporta B and Resche-Rigon M . (1998). Annu. Rev. Physiol, 60, 619–642.

  • Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P and Flavell RA . (1998). Cell, 94, 325–337.

  • Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P and Flavell RA . (1996). Nature, 384, 368–372.

  • Lambert E, Boudot C, Kadri Z, Soula-Rothhut M, Sowa ML, Mayeux P, Hornebeck W, Haye B and Petitfrere E . (2003). Biochem. J., 372, 767–774.

  • Lang F, Lang KS, Wieder T, Myssina S, Birka C, Lang PA, Kaiser S, Kempe D, Duranton C and Huber SM . (2003a). Pflugers Arch., 121, 919–927.

  • Lang KS, Duranton C, Poehlmann H, Myssina S, Bauer C, Lang F, Wieder T and Huber SM . (2003b). Cell Death Differ., 10, 249–256.

  • Lang KS, Myssina S, Brand V, Sandu C, Lang PA, Berchtold S, Huber SM, Lang F and Wieder T . (2004). Cell Death Differ., 11, 231–243.

  • Lee CY and Baehrecke EH . (2000). Cell Res., 10, 193–204.

  • Lee CY, Clough EA, Yellon P, Teslovich TM, Stephan DA and Baehrecke EH . (2003). Curr. Biol., 13, 350–357.

  • Lemasters JJ, Qian T, Elmore SP, Trost LC, Nishimura Y, Herman B, Bradham CA, Brenner DA and Nieminen AL . (1998). Biofactors, 8, 283–285.

  • Lemasters JJ, Qian T, He L, Kim JS, Elmore SP, Cascio WE and Brenner DA . (2002). Antioxid. Redox Signal., 4, 769–781.

  • Lippens S, Kockx M, Knaapen M, Mortier L, Polakowska R, Verheyen A, Garmyn M, Zwijsen A, Formstecher P, Huylebroeck D, Vandenabeele P and Declercq W . (2000). Cell Death Differ., 7, 1218–1224.

  • Lockshin RA . (1969). Lysosomes in Biology and Pathology, Dingle JT and Fell HB (eds). North-Holland Publishing: Amsterdam, pp. 363–391.

    Google Scholar 

  • Lockshin RA and Zakeri Z . (2001). Nat. Rev. Mol. Cell. Biol, 2, 545–550.

  • Macho A, Hirsch T, Marzo I, Marchetti P, Dallaporta B, Susin SA, Zamzami N and Kroemer G . (1997). J. Immunol., 158, 4612–4619.

  • Mammone T, Gan D, Collins D, Lockshin RA, Marenus K and Maes D . (2000). Cell Biol. Toxicol., 16, 293–302.

  • Mammone T, Marenus K, Maes D and Lockshin RA . (1998). Skin Pharmacol. Appl. Skin Physiol., 11, 152–160.

  • Manolagas SC . (2000). Endocr. Rev., 21, 115–137.

  • Miller TM, Moulder KL, Knudson CM, Creedon DJ, Deshmukh M, Korsmeyer SJ, and Johnson EM and Jr . (1997). J. Cell Biol., 139, 205–217.

  • Mogi M and Togari A . (2003). J. Biol. Chem., 278, 47477–47482.

  • Mori M, Uchida M, Watanabe T, Kirito K, Hatake K, Ozawa K and Komatsu N . (2003). J. Cell Physiol., 195, 290–297.

  • Norsgaard H, Glenting M, Kristensen P, Clark BFC and Rattan SIS . (1994). Arch. Gerontol. Geriat., 18, 185–196.

  • Oppenheim RW, Flavell RA, Vinsant S, Prevette D, Kuan CY and Rakic P . (2001). J. Neurosci., 21, 4752–4760.

  • Perfettini JL and Kroemer G . (2003). Nat. Immunol., 4, 308–310.

  • Polakowska RR, Piacentini M, Bartlett R, Goldsmith LA and Haake AR . (1994). Dev. Dyn., 199, 176–188.

  • Print CG and Loveland KL . (2000). BioEssays, 22, 423–430.

  • Raff MC, Whitmore AV and Finn JT . (2002). Science, 296, 868–871.

  • Sanchez-Prieto R, Lleonart M and Cajal SRY . (1995). Oncogene, 11, 675–682.

  • Sanders EJ and Parker E . (2002). J. Anat., 201, 121–135.

  • Sanders EJ and Parker E . (2003). Differentiation, 71, 425–433.

  • Sasaki K, Iwatsuki H, Suda M and Itano C . (1993). J. Anat., 183, 113–120.

  • Schotte P, Declercq W, Van Huffel S, Vandenabeele P and Beyaert R . (1999). FEBS Lett., 442, 117–121.

  • Schweichel JU and Merker HJ . (1973). Teratology, 7, 253–266.

  • Sinha Hikim AP, Lue Y, Diaz-Romero M, Yen PH, Wang C and Swerdloff RS . (2003). J. Steroid Biochem. Mol. Biol., 85, 175–182.

  • Smith FF, Mertz JR, Krebs I, Tres LL, Chae CB, Zakeri Z, Engelhardt J, Hoover D, Tenniswood M and Kierszenbaum AL . (1992). Mol. Reprod. Dev., 33, 363–372.

  • Sordet O, Rebe C, Plenchette S, Zermati Y, Hermine O, Vainchenker W, Garrido C, Solary E and Dubrez-Daloz L . (2002). Blood, 100, 4446–4453.

  • Sun JS, Huang YC, Lin FH and Chen LT . (2003). J. Biomed. Mater. Res., 64A, 616–621.

  • Tamada Y, Takama H, Kitamura T, Yokochi K, Nitta Y, Ikeya T and Matsumoto Y . (1994). Br. J. Dermatol., 131, 521–524.

  • Tolkovsky AM, Xue L, Fletcher GC and Borutaite V . (2002). Biochimie, 84, 233–240.

  • Torriglia A, Chaudun E, Chany-Fournier F, Courtois Y and Counis MF . (2001). Exp. Eye Res., 72, 443–453.

  • Vaux DL, Whitney D and Weissman IL . (1996). Microsc. Res. Technol., 34, 259–266.

  • Weber R . (1969). Lysosomes in Biology and Pathology, Vol. I. Dingle JT and Fell HB (eds). Elsevier, North-Holland: Amsterdam, pp. 437–461.

    Google Scholar 

  • Weil M, Raff MC and Braga VM . (1999). Curr. Biol, 9, 361–364.

  • Weinberg WC, Azzoli CG, Chapman K, Levine AJ and Yuspa SH . (1995). Oncogene, 10, 2271–2279.

  • Weisfelner ME and Gottlieb AB . (2003). J. Drugs Dermatol., 2, 385–391.

  • Wride MA . (2000). Apoptosis, 5, 203–209.

  • Wride MA, Parker E and Sanders EJ . (1999). Dev. Biol., 213, 142–156.

  • Xue D, Shaham S and Horvitz HR . (1996). Genes Dev., 10, 1073–1083.

  • Xue L, Fletcher GC and Tolkovsky AM . (1999). Mol. Cell Neurosci., 14, 180–198.

  • Xue L, Fletcher GC and Tolkovsky AM . (2001). Curr. Biol., 11, 361–365.

  • Yao K, Wang K, Xu W, Sun Z, Shentu X and Qiu P . (2003). Chin. Med. J. (Engl.), 116, 1034–1038.

  • Yuan J and Horvitz HR . (1990). Dev. Biol., 138, 33–41.

  • Zakeri Z, Alles A, Xia P, Yesner L, Kodaman N and Lockshin RA . (1990). J. Cell Biol., 111, 337.

  • Zakeri Z, Curto M, Hoover D, Wightman K, Engelhardt J, Smith FF, Kierszenbaum AL, Gleeson T and Tenniswood M . (1992). Mol. Reprod. Dev., 33, 373–384.

  • Zakeri ZF, Quaglino D, Latham T and Lockshin RA . (1993). FASEB J., 7, 470–478.

  • Zamzami N, Hirsch T, Dallaporta B, Petit PX and Kroemer G . (1997). J. Bioenerg. Biomembr., 29, 185–193.

  • Zhuang S, Ouedraogo GD and Kochevar IE . (2003). Oncogene, 22, 4413–4424.

Download references

Acknowledgements

The electron micrographs were taken in collaborative research with Daniela Quaglino (Figure 2a) and Martin Tenniswood (Figures 2b and c). The research quoted of Javier Negrón, Caroline Facey, and Nathaniel Abraham was carried out as part of their research, supported respectively by GANN, IMSD from the National Institutes of Health, and St John's University.

Author information

Authors and Affiliations

  1. Department of Biology, Queens College and Graduate Center of the City University of New York, 65-30 Kissena Blvd., Flushing, 11367, NY, USA

    Richard A Lockshin

  2. Department of Biological Sciences, St John's University, 8000 Utopia Parkway, 11439, NY, Jamaica, USA

    Zahra Zakeri

Authors
  1. Richard A Lockshin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zahra Zakeri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard A Lockshin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lockshin, R., Zakeri, Z. Caspase-independent cell death?. Oncogene 23, 2766–2773 (2004). https://doi.org/10.1038/sj.onc.1207514

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207514

Keywords

This article is cited by

Search

Advanced search

Quick links