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. 1992 Oct 1;176(4):1043–1051. doi: 10.1084/jem.176.4.1043

Interleukin 3 protects murine bone marrow cells from apoptosis induced by DNA damaging agents

PMCID: PMC2119402  PMID: 1402650

Abstract

Murine bone marrow-derived cells, dependent on interleukin 3 (IL-3) for their growth in culture, undergo programmed cell, or apoptosis, upon cytokine withdrawal. Here it is reported that a variety of DNA damaging agents cause a more rapid onset of apoptosis in a factor-dependent cell line, BAF3, deprived of IL-3. In contrast, when cultured in the presence of IL-3, or other growth promoting factors, BAF3 cells are highly resistant to X-irradiation and the cytotoxic drugs etoposide and cisplatin. Overexpression of the bcl2 gene product also protects BAF3 cells from DNA damage. The presence of IL-3 is not required during the initial events of DNA damage or its repair. In the absence of IL-3, cells still complete the repair of DNA breaks within 15 min, and continue to cycle for 5 h. At this time, IL-3 is necessary to prevent the accelerated onset of DNA cleavage from a G2 arrest point.

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Selected References

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  1. Bardon S., Vignon F., Montcourrier P., Rochefort H. Steroid receptor-mediated cytotoxicity of an antiestrogen and an antiprogestin in breast cancer cells. Cancer Res. 1987 Mar 1;47(5):1441–1448. [PubMed] [Google Scholar]
  2. Berger N. A. Poly(ADP-ribose) in the cellular response to DNA damage. Radiat Res. 1985 Jan;101(1):4–15. [PubMed] [Google Scholar]
  3. Bradley M. O., Kohn K. W. X-ray induced DNA double strand break production and repair in mammalian cells as measured by neutral filter elution. Nucleic Acids Res. 1979 Oct 10;7(3):793–804. doi: 10.1093/nar/7.3.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Eastman A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacol Ther. 1987;34(2):155–166. doi: 10.1016/0163-7258(87)90009-x. [DOI] [PubMed] [Google Scholar]
  5. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  6. Kemp L. M., Sedgwick S. G., Jeggo P. A. X-ray sensitive mutants of Chinese hamster ovary cells defective in double-strand break rejoining. Mutat Res. 1984 Nov-Dec;132(5-6):189–196. doi: 10.1016/0167-8817(84)90037-3. [DOI] [PubMed] [Google Scholar]
  7. Koyasu S., Tojo A., Miyajima A., Akiyama T., Kasuga M., Urabe A., Schreurs J., Arai K., Takaku F., Yahara I. Interleukin 3-specific tyrosine phosphorylation of a membrane glycoprotein of Mr 150,000 in multi-factor-dependent myeloid cell lines. EMBO J. 1987 Dec 20;6(13):3979–3984. doi: 10.1002/j.1460-2075.1987.tb02740.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lee F., Yokota T., Otsuka T., Gemmell L., Larson N., Luh J., Arai K., Rennick D. Isolation of cDNA for a human granulocyte-macrophage colony-stimulating factor by functional expression in mammalian cells. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4360–4364. doi: 10.1073/pnas.82.13.4360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Liu L. F. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem. 1989;58:351–375. doi: 10.1146/annurev.bi.58.070189.002031. [DOI] [PubMed] [Google Scholar]
  10. Liu Y. J., Joshua D. E., Williams G. T., Smith C. A., Gordon J., MacLennan I. C. Mechanism of antigen-driven selection in germinal centres. Nature. 1989 Dec 21;342(6252):929–931. doi: 10.1038/342929a0. [DOI] [PubMed] [Google Scholar]
  11. Mann R., Mulligan R. C., Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. doi: 10.1016/0092-8674(83)90344-6. [DOI] [PubMed] [Google Scholar]
  12. Murphy K. M., Heimberger A. B., Loh D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 1990 Dec 21;250(4988):1720–1723. doi: 10.1126/science.2125367. [DOI] [PubMed] [Google Scholar]
  13. Neta R., Douches S., Oppenheim J. J. Interleukin 1 is a radioprotector. J Immunol. 1986 Apr 1;136(7):2483–2485. [PubMed] [Google Scholar]
  14. Neta R., Oppenheim J. J. Radioprotection with cytokines--learning from nature to cope with radiation damage. Cancer Cells. 1991 Oct;3(10):391–396. [PubMed] [Google Scholar]
  15. Nuñez G., London L., Hockenbery D., Alexander M., McKearn J. P., Korsmeyer S. J. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990 May 1;144(9):3602–3610. [PubMed] [Google Scholar]
  16. Palacios R., Steinmetz M. Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell. 1985 Jul;41(3):727–734. doi: 10.1016/s0092-8674(85)80053-2. [DOI] [PubMed] [Google Scholar]
  17. Pezzella F., Tse A. G., Cordell J. L., Pulford K. A., Gatter K. C., Mason D. Y. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990 Aug;137(2):225–232. [PMC free article] [PubMed] [Google Scholar]
  18. Rodriguez-Tarduchy G., Collins M., López-Rivas A. Regulation of apoptosis in interleukin-3-dependent hemopoietic cells by interleukin-3 and calcium ionophores. EMBO J. 1990 Sep;9(9):2997–3002. doi: 10.1002/j.1460-2075.1990.tb07492.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rodriguez-Tarduchy G., Malde P., Lopez-Rivas A., Collins M. K. Inhibition of apoptosis by calcium ionophores in IL-3-dependent bone marrow cells is dependent upon production of IL-4+. J Immunol. 1992 Mar 1;148(5):1416–1422. [PubMed] [Google Scholar]
  20. Sellins K. S., Cohen J. J. Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J Immunol. 1987 Nov 15;139(10):3199–3206. [PubMed] [Google Scholar]
  21. Sentman C. L., Shutter J. R., Hockenbery D., Kanagawa O., Korsmeyer S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. doi: 10.1016/0092-8674(91)90361-2. [DOI] [PubMed] [Google Scholar]
  22. Shimizu T., Kubota M., Tanizawa A., Sano H., Kasai Y., Hashimoto H., Akiyama Y., Mikawa H. Inhibition of both etoposide-induced DNA fragmentation and activation of poly(ADP-ribose) synthesis by zinc ion. Biochem Biophys Res Commun. 1990 Jun 29;169(3):1172–1177. doi: 10.1016/0006-291x(90)92019-v. [DOI] [PubMed] [Google Scholar]
  23. Sonoda Y., Yang Y. C., Wong G. G., Clark S. C., Ogawa M. Erythroid burst-promoting activity of purified recombinant human GM-CSF and interleukin-3: studies with anti-GM-CSF and anti-IL-3 sera and studies in serum-free cultures. Blood. 1988 Oct;72(4):1381–1386. [PubMed] [Google Scholar]
  24. Sorenson C. M., Barry M. A., Eastman A. Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin. J Natl Cancer Inst. 1990 May 2;82(9):749–755. doi: 10.1093/jnci/82.9.749. [DOI] [PubMed] [Google Scholar]
  25. Strasser A., Harris A. W., Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. doi: 10.1016/0092-8674(91)90362-3. [DOI] [PubMed] [Google Scholar]
  26. Tobey R. A. Different drugs arrest cells at a number of distinct stages in G2. Nature. 1975 Mar 20;254(5497):245–247. doi: 10.1038/254245a0. [DOI] [PubMed] [Google Scholar]
  27. Van Zant G. Studies of hematopoietic stem cells spared by 5-fluorouracil. J Exp Med. 1984 Mar 1;159(3):679–690. doi: 10.1084/jem.159.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Whetton A. D., Huang S. J., Monk P. N. Adenosine triphosphate can maintain multipotent haemopoietic stem cells in the absence of interleukin 3 via a membrane permeabilization mechanism. Biochem Biophys Res Commun. 1988 May 16;152(3):1173–1178. doi: 10.1016/s0006-291x(88)80408-x. [DOI] [PubMed] [Google Scholar]
  29. 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]

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