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Acute expression of RET/PTC induces isozyme-specific activation and subsequent downregulation of PKCɛ in PCCL3 thyroid cells

Oncogene volume 22, pages 6830–6838 (2003)Cite this article

Abstract

Most papillary thyroid carcinomas (PTC) have an isozyme-specific reduction of protein kinase C (PKC)ɛ, which occurs through a post-transcriptional mechanism. Here, we test whether the oncoprotein RET/PTC could be responsible for this effect, since RET/PTC rearrangements are quite prevalent in PTC and RET/PTC activates PLCγ, an upstream modulator of PKCs. At 3 h after induction of RET/PTC1 or RET/PTC3 expression, there was evidence of PKCɛ activation. Activation was restricted to PKCɛ, as acute expression of RET/PTC did not change the subcellular distribution of other PKC isozymes expressed in PCCL3 cells. Prolonged RET/PTC expression (2–6 days) produced an isozyme-specific change in PKCɛ subcellular localization and a decrease in total PKCɛ levels. The expression of RET/PTC3Y541F, which does not interact with PLCγ, but signals normally through other RET effectors, had no effect on PKCɛ distribution at any of the time points examined. However, downregulation of total PKCɛ levels was only partially prevented by expression of RET/PTCY541F. Cells with decreased PKCɛ following prolonged expression of RET/PTC were relatively resistant to doxorubicin-induced apoptosis. Based on our previous observation that PCCL3 cells expressing a dominant-negative PKCɛ are also markedly resistant to apoptosis, we propose that selective downregulation of PKCɛ following prolonged RET/PTC activation promotes cell survival and clonal expansion.

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Acknowledgements

This work was supported in part by NIH Grants CA50706 and CA72597 (JAF), and K01DK02781 (JAK).

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  1. Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Mail Location 0547, Cincinnati, 45267, OH, USA

    Jeffrey A Knauf, Bin Ouyang, Mickey Croyle, Edna Kimura & James A Fagin

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  1. Jeffrey A Knauf
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  2. Bin Ouyang
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Correspondence to Jeffrey A Knauf.

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Knauf, J., Ouyang, B., Croyle, M. et al. Acute expression of RET/PTC induces isozyme-specific activation and subsequent downregulation of PKCɛ in PCCL3 thyroid cells. Oncogene 22, 6830–6838 (2003). https://doi.org/10.1038/sj.onc.1206829

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