Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1995 Oct 15;311(Pt 2):585–588. doi: 10.1042/bj3110585

The 2-chlorodeoxyadenosine-induced cell death signalling pathway in human thymocytes is different from that induced by 2-chloroadenosine.

Z Szondy 1
PMCID: PMC1136039  PMID: 7487899

Abstract

2-chloroadenosine induced DNA fragmentation and cell death in human thymocytes primarily by Ca(2+)-dependent mechanisms. Incubation of human thymocytes with 2-chlorodeoxyadenosine (5-1000 nM) also induced cell death (apoptosis) which was dependent on macromolecule synthesis and involved activation of an endonuclease which was inhibited by Zn2+. The effect of 2-chlorodeoxyadenosine was prevented by addition of dipyridamole, a strong nucleoside transport inhibitor, or of deoxycytidine, previously shown to compete for uptake by deoxycytidine kinase. 2-Chlorodeoxyadenosine-induced apoptosis did not involve increases in the cytosolic Ca2+ concentration, but required the presence of intracellular Ca2+. It was not inhibited by activators of protein kinase C previously shown to inhibit Ca(2+)-dependent cell death. Addition of 2-chlorodeoxyadenosine induced an increase in the amount of p53 in human thymocytes, while 2-chloroadenosine had no effect. These data suggest that 2-chloroadenosine and 2-chlorodeoxyadenosine induce cell death in human thymocytes via different signalling pathways.

Full text

PDF
585

Images in this article

586Figure 1
on p.586
587Figure 2
on p.587

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arends M. J., Morris R. G., Wyllie A. H. Apoptosis. The role of the endonuclease. Am J Pathol. 1990 Mar;136(3):593–608. [PMC free article] [PubMed] [Google Scholar]
  2. Aw T. Y., Nicotera P., Manzo L., Orrenius S. Tributyltin stimulates apoptosis in rat thymocytes. Arch Biochem Biophys. 1990 Nov 15;283(1):46–50. doi: 10.1016/0003-9861(90)90610-b. [DOI] [PubMed] [Google Scholar]
  3. BURTON K. A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J. 1956 Feb;62(2):315–323. doi: 10.1042/bj0620315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carson D. A., Wasson D. B., Beutler E. Antileukemic and immunosuppressive activity of 2-chloro-2'-deoxyadenosine. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2232–2236. doi: 10.1073/pnas.81.7.2232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  6. Cohen J. J., Duke R. C. Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol. 1984 Jan;132(1):38–42. [PubMed] [Google Scholar]
  7. Fesus L., Davies P. J., Piacentini M. Apoptosis: molecular mechanisms in programmed cell death. Eur J Cell Biol. 1991 Dec;56(2):170–177. [PubMed] [Google Scholar]
  8. Hirota Y., Yoshioka A., Tanaka S., Watanabe K., Otani T., Minowada J., Matsuda A., Ueda T., Wataya Y. Imbalance of deoxyribonucleoside triphosphates, DNA double-strand breaks, and cell death caused by 2-chlorodeoxyadenosine in mouse FM3A cells. Cancer Res. 1989 Feb 15;49(4):915–919. [PubMed] [Google Scholar]
  9. Kaiser N., Edelman I. S. Calcium dependence of glucocorticoid-induced lymphocytolysis. Proc Natl Acad Sci U S A. 1977 Feb;74(2):638–642. doi: 10.1073/pnas.74.2.638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kass G. E., Duddy S. K., Moore G. A., Orrenius S. 2,5-Di-(tert-butyl)-1,4-benzohydroquinone rapidly elevates cytosolic Ca2+ concentration by mobilizing the inositol 1,4,5-trisphosphate-sensitive Ca2+ pool. J Biol Chem. 1989 Sep 15;264(26):15192–15198. [PubMed] [Google Scholar]
  11. Kizaki H., Shimada H., Ohsaka F., Sakurada T. Adenosine, deoxyadenosine, and deoxyguanosine induce DNA cleavage in mouse thymocytes. J Immunol. 1988 Sep 1;141(5):1652–1657. [PubMed] [Google Scholar]
  12. Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
  13. Malgaroli A., Milani D., Meldolesi J., Pozzan T. Fura-2 measurement of cytosolic free Ca2+ in monolayers and suspensions of various types of animal cells. J Cell Biol. 1987 Nov;105(5):2145–2155. doi: 10.1083/jcb.105.5.2145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McConkey D. J., Hartzell P., Amador-Pérez J. F., Orrenius S., Jondal M. Calcium-dependent killing of immature thymocytes by stimulation via the CD3/T cell receptor complex. J Immunol. 1989 Sep 15;143(6):1801–1806. [PubMed] [Google Scholar]
  15. McConkey D. J., Hartzell P., Duddy S. K., Håkansson H., Orrenius S. 2,3,7,8-Tetrachlorodibenzo-p-dioxin kills immature thymocytes by Ca2+-mediated endonuclease activation. Science. 1988 Oct 14;242(4876):256–259. doi: 10.1126/science.3262923. [DOI] [PubMed] [Google Scholar]
  16. McConkey D. J., Hartzell P., Jondal M., Orrenius S. Inhibition of DNA fragmentation in thymocytes and isolated thymocyte nuclei by agents that stimulate protein kinase C. J Biol Chem. 1989 Aug 15;264(23):13399–13402. [PubMed] [Google Scholar]
  17. Pizzo P., Zanovello P., Bronte V., Di Virgilio F. Extracellular ATP causes lysis of mouse thymocytes and activates a plasma membrane ion channel. Biochem J. 1991 Feb 15;274(Pt 1):139–144. doi: 10.1042/bj2740139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Plunkett W., Saunders P. P. Metabolism and action of purine nucleoside analogs. Pharmacol Ther. 1991;49(3):239–268. doi: 10.1016/0163-7258(91)90057-s. [DOI] [PubMed] [Google Scholar]
  19. Satoh M. S., Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature. 1992 Mar 26;356(6367):356–358. doi: 10.1038/356356a0. [DOI] [PubMed] [Google Scholar]
  20. Seto S., Carrera C. J., Kubota M., Wasson D. B., Carson D. A. Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest. 1985 Feb;75(2):377–383. doi: 10.1172/JCI111710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Szondy Z. Adenosine stimulates DNA fragmentation in human thymocytes by Ca(2+)-mediated mechanisms. Biochem J. 1994 Dec 15;304(Pt 3):877–885. doi: 10.1042/bj3040877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wyllie A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES