Abstract
The thyroid gland is one of the most sensitive organs in ionizing radiation (IR)-induced carcinogenesis. To determine, therefore, the specific cascade of IR-induced signal transduction in human thyroid cells, we investigated the functional role of protein kinase C (PKC), especially its interlocking activation of c-Jun NH2-terminal kinase (JNK) pathway. In the present study, using adenovirus expression vectors for diverse dominant-negative (DN) types of PKC isoforms (α, β2, δ, ε and ζ) expressed in primary cultured human thyroid cells, only DN/PKC δ suppressed IR-induced JNK activation. In addition, Rottlerin, a PKC δ specific inhibitor, inhibited IR-induced JNK activation. IR-induced activation of transcription factor AP-1, downstream target of JNK, was also attenuated by DN/PKC δ. To examine the involvement of upstream kinases of JNK, we performed immune-complex kinase assays of mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. IR activated MKK7 but not MKK4, and this activation was inhibited by Rottlerin. Furthermore, IR-induced JNK activation was suppressed by overexpression of kinase-deficient MKK7. Our results indicate that IR selectively activates the cascade of PKC δ-MKK7-JNK-AP-1 in human thyroid cells, suggesting a not apoptotic but radio-resistant role of PKC δ in human thyroid cells following IR.
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Acknowledgements
We thank Dr RJ Davis (Howard Hughes Medical Institute, University of Massachusetts Medical School) and Dr H Ito (National Children's Medical Research Center, Tokyo) for supplying the plasmids.
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Mitsutake, N., Namba, H., Shklyaev, S. et al. PKC δ mediates ionizing radiation-induced activation of c-Jun NH2-terminal kinase through MKK7 in human thyroid cells. Oncogene 20, 989–996 (2001). https://doi.org/10.1038/sj.onc.1204179
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DOI: https://doi.org/10.1038/sj.onc.1204179
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