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Analysis of mechanisms involved in the prevention of γ irradiation-induced apoptosis by hGM-CSF

Oncogene volume 19, pages 571–579 (2000)Cite this article

Abstract

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) induces proliferation and sustains viability of the mouse interleukin (IL)-3 dependent lymphoid cell line BA/F3 expressing the hGM-CSF receptor. Caspase-3 like enzyme activity and DNA fragmentation were augmented by depletion of this factor from the cell, and exposure to γ irradiation accelerated kinetics of these events. Anti γ irradiation-induced apoptosis occurred through various mutant GM-CSF receptors and only the box1 region was essential while the C terminal region, including tyrosine residues which are required for MAPK cascade activation, was dispensable. Consistent with this notion, the addition of PD98059 had no effect on this activity thereby indicating that activation of MAPK is not essential for the activity. As expected, γ irradiation increased p53 protein and bax mRNA levels and the presence of hGM-CSF dramatically modulated bax/bcl-XL ratio. The PI-3K specific inhibitor wortmannin did not affect hGM-CSF dependent anti γ irradiation induced apoptosis nor bcl-XL induction, thus bcl-XL but not PI-3K pathway seems to be involved in hGM-CSF dependent anti γ irradiation-induced apoptosis. It is well documented that the box1 region is essential for GM-CSF dependent activation of JAK2 and JAK2 specific inhibitor AG490 suppressed anti γ irradiation-induced apoptosis by hGM-CSF. An artificial JAK2 activating molecule in which extracellular and the transmembrane of βc fused with whole JAK2 can sustain BA/F3 cells survival and proliferation mIL-3 independently, but these cells are susceptible to γ irradiation. Furthermore GyrB/Jak2, which can activate STAT5 but not the MAPK cascade nor survival of BA/F3 cells, also could not prevent γ irradiation-induced apoptosis. Although JAK2 is essential for hGM-CSF dependent anti γ irradiation-induced apoptosis, it appeared that JAK2 does not seem sufficient for the activity.

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Acknowledgements

We thank Kayo Hagino, Kumiko Nakada, Yukitaka Izawa and Yutaka Aoki for excellent technical support, and Drs Tohru Itoh and Marty Dahl for helpful discussion.

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Authors and Affiliations

  1. Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Japan

    Rui Liu, Chang-Bai Liu, Mohammad Golam Mohi, Ken-ichi Arai & Sumiko Watanabe

  2. CREST, Japan Science and Technology Corporation (JST), 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan

    Ken-ichi Arai

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  1. Rui Liu
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Liu, R., Liu, CB., Mohi, M. et al. Analysis of mechanisms involved in the prevention of γ irradiation-induced apoptosis by hGM-CSF. Oncogene 19, 571–579 (2000). https://doi.org/10.1038/sj.onc.1203364

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