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RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase

Oncogene volume 22, pages 4406–4412 (2003)Cite this article

Abstract

Constitutive activation of the RET proto-oncogene in papillary thyroid carcinomas results from rearrangements linking the promoter(s) and N-terminal domains of unrelated genes to the C-terminus of RET tyrosine kinase (RET/PTC). RET/PTC expression has been demonstrated to inhibit transcription of thyroid-specific genes. To study the signal transduction pathways responsible for this, we generated PCCL3 thyroid cells with doxycycline-inducible expression of RET/PTC3, RET/PTC3Y541F, or PTC2/PDZ. Acute expression of RET/PTCY541F appropriately interacted with Shc, an intermediate in the activation of the Ras pathway, but failed to activate PLCγ. By contrast, PTC2/PDZ failed to bind Shc, but interacted normally with PLCγ. Acute expression of RET/PTC3 or RET/PTC3Y541F, but not PTC2/PDZ, inhibited TSH-induced Tg and NIS expression, suggesting that activation of Shc-Ras, but not PLCγ, is required for RET/PTC-induced dedifferentiation. Accordingly, acute expression of H-RasV12 or of a constitutively active MEK1 also blocked TSH-induced expression of Tg and NIS. Moreover, MEK inhibitors restored Tg and NIS levels. In conclusion, activation of the Ras/Raf/MEK/MAPK pathway through Shc mediates RET/PTC-induced thyroid cell dedifferentiation. This suggests that inhibition of this pathway may promote redifferentiation in poorly differentiated thyroid carcinomas with constitutive activation of either Ras or RET/PTC.

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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, Cincinnati, 45267, OH, USA

    Jeffrey A Knauf, Hiroaki Kuroda, Saswata Basu & James A Fagin

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  1. Jeffrey A Knauf
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Correspondence to Jeffrey A Knauf.

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Knauf, J., Kuroda, H., Basu, S. et al. RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Oncogene 22, 4406–4412 (2003). https://doi.org/10.1038/sj.onc.1206602

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