Abstract
The TEL/PDGFRβ (T/P) fusion protein isolated from patients bearing a t(5;12) translocation is transforming when expressed in haematopoietic cells. To examine the signal transduction events activated by this protein, we measured the effect of T/P on activation of the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) in mouse bone marrow-derived Ba/F3 cells. Significant increase in the activity of JNK/SAPK1 was observed in transient transfection as well as in Ba/F3 cells stably expressing T/P. This activation was abrogated when the T/P-expressing cells were treated with a specific inhibitor of the PDGFRβ tyrosine kinase, indicating that the activity of the PDGFRβ part of the fusion protein was involved in JNK/SAPK activation. Expression of a dominant negative mutant of mitogen-activated protein kinase kinase 4 (MKK4), a direct activator of JNK/SAPK, prevented T/P-induced JNK/SAPK activation. In addition, inhibition of phosphoinositide-3 OH kinase (PI-3 kinase), a promoting survival factor, potentiated the effect of T/P on JNK/SAPK activation. Interestingly, expression of T/P was shown to initiate an apoptotic response that was enhanced by treatment of cells with the PI-3 kinase inhibitor LY294002, suggesting that T/P mediated cell death through activation of JNK/SAPK signalling pathway. Consistent with this hypothesis, expression of the dominant negative mutant of MKK4 decreased T/P-mediated apoptosis, while a dominant-negative mutant of PI-3 kinase enhances cell death. These findings indicate that activation of JNK/SAPK by T/P is related to apoptosis rather than cell proliferation and transformation.
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Acknowledgements
We thank Drs R Davis, T Golub, S Gutkind, A Hall, H Ichijo, M Karin, and H Shibuya for providing reagents. This work was supported by INSERM (Institut National de la Santé et de la Recherche Médicale) and ARC (Association pour la Recherche sur le Cancer). A Atfi was a recipient of grants from la Ligue contre le Cancer and la Ligue contre le Cancer Comité de Paris, he is also a CNRS investigator.
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Atfi, A., Prunier, C., Mazars, A. et al. The oncogenic TEL/PDGFRβ fusion protein induces cell death through JNK/SAPK pathway. Oncogene 18, 3878–3885 (1999). https://doi.org/10.1038/sj.onc.1202734
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DOI: https://doi.org/10.1038/sj.onc.1202734