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PKC δ mediates ionizing radiation-induced activation of c-Jun NH2-terminal kinase through MKK7 in human thyroid cells

Oncogene volume 20, pages 989–996 (2001)Cite this article

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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Authors and Affiliations

  1. Department of Nature Medicine, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Nagasaki, 852-8523, Japan

    Norisato Mitsutake, Hiroyuki Namba, Stanislav S Shklyaev, Akira Ohtsuru & Shunichi Yamashita

  2. 1st Department of Surgery, Nagasaki University School of Medicine, Nagasaki, 852-8523, Japan

    Norisato Mitsutake & Hiroyoshi Ayabe

  3. 1st Department of Anatomy, Nagasaki University School of Medicine, Nagasaki, 852-8523, Japan

    Tomoo Tsukazaki

  4. Institute of Molecular Oncology, Showa University, Tokyo, 142-8555, Japan

    Motoi Ohba & Toshio Kuroki

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  1. Norisato Mitsutake
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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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