Cell Volume Regulation, Ions, and Apoptosis

  • Carl D. Bortner
  • Francis M. HughesJr.
  • John A. Cidlowski


It is generally accepted that all cells have the ability to undergo an internally controlled cell suicide process known as apoptosis, or programmed cell death, in response to a given stimulus or environmental agent39. The apoptotic process efficiently removes or eliminates a population of unwanted cells from the body at a given time in the absence of an inflammatory response. This mode of cell death has been observed during development25,37,40, in the immune system2, and in the progression of both AIDS21,33,34 and cancer24,35,38. Apoptosis is characterized by a distinct set of morphological and biochemical features including cell shrinkage, nuclear condensation, proteolysis, internucleosomal DNA cleavage, and apoptotic body formation27. Over the past 20 years, much attention has focused on the biochemical aspects of apoptosis, including the intracellular signals leading to cell death, the enzymes involved in both protein and DNA degradation, and the role several apoptotic modulating genes play to control or inhibit cell death12. However, of all the characteristics which define this mode of cell death, the observation that the cells shrink or lose volume during apoptosis has remained relatively unexplored.


Cell Volume Cell Shrinkage Regulatory Volume Decrease Cell Death Process Cell Volume Regulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Al-Habori, M. Cell volume and ion transport regulation. Int. J. Biochem. 1994; 26:319–34.PubMedCrossRefGoogle Scholar
  2. 2.
    Allen PD, Bustin SA, and Newland AC. The role of apoptosis (programmed cell death) in haemopoiesis and the immune system. Blood Rev. 1993; 7:63–73.PubMedCrossRefGoogle Scholar
  3. 3.
    Barbiero G, Duranti F, Bonelli G, Amenta JS, and Baccino FM. Intracellular ionic variations in the apoptotic death of L cells by inhibitors of cell cycle progression. Expt. Cell Res. 1995; 217:410–8.CrossRefGoogle Scholar
  4. 4.
    Barinaga M. Cell sucide: by ICE, not fire. Science. 1994; 263:754–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Beauvais F, Michel L, and Dubertret L. Human eosinophils in culture undergo a striking and rapid shrinkage during apoptosis. Role of K+ channels. J. Leukoc. Biol. 1995; 57:851–5.PubMedGoogle Scholar
  6. 6.
    Benson RSP, Heer S, Dive C., and Watson AJM. Characteristics of cell volume loss in CEM-C7A cells during dexamethasone-induced apoptosis. Am. J. Physiol. 1996; 270:C1190-1203.Google Scholar
  7. 7.
    Black RA, Kronheim SR and Sleath PR. Activation of interleukin-1 beta by a co-induced protease. FEBS Lett. 1989; 247:386–390.PubMedCrossRefGoogle Scholar
  8. 8.
    Bortner CD, and Cidlowski JA. The absence of volume regulatory mechanisms contributes to the rapid activation of apoptosis in thymocytes. Am. J. Physiol. 1996, 271:C950–61.PubMedGoogle Scholar
  9. 9.
    Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van-Ness K, Greenstreet TA, March CJ, Kronheim SR, Druk T, Cannizzaro LA, Huebner K, and Black RA. Molecular cloning of the interleukin-1 beta converting enzyme. Science. 1992; 256:97–104.PubMedCrossRefGoogle Scholar
  10. 10.
    Cheung RK, Grinstein S, and Gelfand EW. Volume regulation by human lymphocytes; Identification of differences between the two major lymphocyte subpopulations. J. Clin. Invest. 1992; 70:632–38.CrossRefGoogle Scholar
  11. 11.
    Grinstein S, Clarke CA, and Rothstein A. Activation of Na+/H+ exchange in lymphocytes by osmoticallyinduced volume changes and by cytoplasmic acidification. J. Gen. Physiol. 1983; 82:619–38.PubMedCrossRefGoogle Scholar
  12. 12.
    Hale AJ, Smith CA, Sutherland LC., Stoneman VEA, Longthorne VL, Culhane AC., and Williams GT. Apoptosis: molecular regulation of cell death. Eur. J. Biochem. 1996; 236:1–26.PubMedCrossRefGoogle Scholar
  13. 13.
    Haussinger D. The role of cellular hydration in the regulation of cell function. Biochem. J. 1996; 313:697–710.PubMedGoogle Scholar
  14. 14.
    Haussinger D, Lang F, and Gerok W. Regulation of cell function by the cellular hydration state. Am. J. Physiol. 1994; 267:E343–55.PubMedGoogle Scholar
  15. 15.
    Hempling HG, Thompson S, and Dupre A. Osmotic properties of human lymphocytes. J. Cell. Physiol. 1977; 93:293–302.PubMedCrossRefGoogle Scholar
  16. 16.
    Hoffmann EK. Volume regulation in cultured cells. Current Topics in Membranes and Transport 1987; 30:125–80.CrossRefGoogle Scholar
  17. 17.
    Hughes FM Jr. and Cidlowski JA. Submitted. 1997.Google Scholar
  18. 18.
    Jonas D, Walev I, Berger T, Liebetrau M., Palmer M and Bhakdi S. Novel path to apoptosis: small transmembrane pores created by staphylococcal alpha-toxin in T lymphocytes evoke internucleosomal DNA degradation. Infect Immun. 1994; 62:1304–12.PubMedGoogle Scholar
  19. 19.
    Kerr JFR., Wyllie AH, and Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 1972; 26:239–57.PubMedCrossRefGoogle Scholar
  20. 20.
    Klassen NV, Walker PR, Ross CK, Cygler J, and Lach B. Two-stage cell shrinkage and the OER for radiation-induced apoptosis of rat thymocytes. Int. J. Radiat. Biol. 1993; 64:571–81.PubMedCrossRefGoogle Scholar
  21. 21.
    Kornbluth RS. Significance of T cell apoptosis for macrophages in HIV infection. J. Leukoc. Biol. 1994; 56:247–56.PubMedGoogle Scholar
  22. 22.
    Kostura MJ, Tocci MJ, Limjuco G, Chin J, Cameron P, Hillman AG, Chartrain NN and Schmidt JA. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci USA. 1989; 85:5227–31.CrossRefGoogle Scholar
  23. 23.
    Kumar S. ICE-like proteases in apoptosis. Trends Biochem Sci. 1995; 20:198–202.PubMedCrossRefGoogle Scholar
  24. 24.
    Lee JM, and Bernstein A. Apoptosis, cancer, and the p53 tumour suppressor gene. Cancer Metastasis Rev. 1995; 14:149–61.PubMedCrossRefGoogle Scholar
  25. 25.
    Lo AC., Houenou LJ, and Oppenheim RW. Apoptosis in the nervous system: morphological features, methods, pathology, and prevention. Arch. Histol. Cytol. 1995; 58:139–49.PubMedCrossRefGoogle Scholar
  26. 26.
    Martin SJ and Green DR. Protease activation during apoptosis, death by a thousand cuts? Cell. 1995; 82:349–52.PubMedCrossRefGoogle Scholar
  27. 27.
    Martin SJ, Green DR, and Cotter TG. Dicing with death: dissecting the components of the apoptotic machinery. Trends Biochem. Sci. 1994; 19:26–30.PubMedCrossRefGoogle Scholar
  28. 28.
    Matthews CC., and Feldman EL. Insulin-like growth factor 1 rescues SH-SY5Y human neuroblastoma cells from hyperosmotic induced programmed cell death. J. Cell. Physiol. 1996; 166:323–31.PubMedCrossRefGoogle Scholar
  29. 29.
    Miura M., Zhu H, Rotello R, Hartwieg EA and Yuan J. Induction of apoptosis in fibroblasts by IL-1 betaconverting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell. 1993; 75:653–60.PubMedCrossRefGoogle Scholar
  30. 30.
    Moule SK, and McGivan JD. Regulation of the plasma membrane potential in hepatocytes — mechanism and physiological significance. Biochim. Biophys. Acta. 1990; 1031:383–97.PubMedCrossRefGoogle Scholar
  31. 31.
    Ohyama H, Yamada T, and Watanabe I. Cell volume reduction associated with interphase death in rat thymocytes. Radiation Res. 1981; 85:333–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Ohyama H, Yamada T, Ohkawa A, and Watanabe I. Radiation-induced formation of apoptotic bodies in rat thymus. Radiation Res. 1985; 101:123–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Orrenius S. Apoptosis: molecular mechanisms and implications for human disease. J. Intern. Med. 1995; 237:529–36.PubMedCrossRefGoogle Scholar
  34. 34.
    Oyaizu N, and Pahwa S. Role of apoptosis in HIV disease pathogenesis. J. Clin. Immunol. 1995; 15:217–31.PubMedCrossRefGoogle Scholar
  35. 35.
    Reed JC. Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr. Opin. Oncol. 1995; 7:541–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Roti-Roti LW, and Rothstein A. Adaptation of mouse leukemic cells (L5178Y) to anisotonic media. I. Cell volume regulation. Exp. Cell Res. 1973; 79:295–310.PubMedCrossRefGoogle Scholar
  37. 37.
    Sanders EJ, and Wride MA. Programmed cell death in development. Int. Rev. Cytol. 1995; 163:105–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Schulte-Hermann R, Bursch W, Grasl-Kraupp B, Torok L, Ellinger A, Mullauer L. Role of active cell death (apoptosis) in multi-stage carcinogenesis. Toxicol. Lett. 1995; 82–83:143–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Schwartzman RA, and Cidlowski JA. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocrine Rev. 1993; 14:133–51.Google Scholar
  40. 40.
    Tata JR. Gene expression during metamorphosis: an ideal model for post-embryonic development. Bioessays 1993; 15:239–48.PubMedCrossRefGoogle Scholar
  41. 41.
    Thomas N, and Bell PA. Glucocorticoid-induced cell-size changes and nuclear fragility in rat thymocytes. Mol. Cell. Endocrinol. 1981; 22:71–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Walev I, Reske K, Palmer M., Valeva A and Bhakdi S. Potassium-inhibited processing of IL-Iβ in human monocytes. EMBO J. 1995; 14:1607–1614.PubMedGoogle Scholar
  43. 43.
    Wu G, and Flynn NE. Regulation of glutamine and glucose metabolism by cell volume in lymphocytes and macrophages. Biochim. Biophys. Acta. 1995; 1243:343–50.PubMedCrossRefGoogle Scholar
  44. 44.
    Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 1980; 284:555–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Wyllie AH, and Morris RG. Hormone-induced cell death. Purification and properties of thymocytes undergoing apoptosis after glucocorticoid treatment. Am. J. Path. 1982; 109:78–87.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Carl D. Bortner
    • 1
  • Francis M. HughesJr.
    • 1
  • John A. Cidlowski
    • 1
  1. 1.The Laboratory of Signal TransductionNational Institute of Environmental Health Sciences, NIHResearch Triangle ParkUSA

Personalised recommendations