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Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors

Oncogene volume 22, pages 4569–4577 (2003)Cite this article

Abstract

Differentiated thyroid carcinomas are the most frequent endocrine neoplasms, but account for few cancer-related deaths. Although the indolent growth of these cancers correlates well with longevity, the biological basis for this good prognosis is not known. In contrast, two of the most frequent autoimmune diseases involve the thyroid suggesting a high propensity for this organ to invoke destructive immunity. Unfortunately, the mechanism linking malignancy and autoimmunity is not clear, although the expression of the oncogenic fusion protein RET/PTC3 (RP3) in both of these disorders may provide a clue. Interestingly, the signaling caused by activated RET kinase involves overlapping pathways and some common to the inflammatory response. Accordingly, we analyzed the function of RP3 and a mutant RP3 molecule to induce proinflammatory pathways in thyroid epithelial cells. Indeed, we find that RP3 alone causes increases in nuclear NF-κB activity and secretion of MCP-1 and GM-CSF. Finally, transfer of RP3-expressing thyrocytes into mice in vivo attracted dense macrophage infiltrates, which lead to rapid thyroid cell death. Further, cytokine synthesis and inflammation was largely abrogated by mutation of RP3 Tyr588; an important protein-binding site for downstream signaling. Together, these studies implicate oncogene-induced cytokine-signaling pathways in a new mechanism linking inflammation with cancer.

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Acknowledgements

We are grateful to B Perussia for reading the manuscript. This work was supported in part by grants from the National Institutes of Health, CA-76259 (JLR), T32-CA09678 (JPR) and the Italian Association for Cancer Research (AIRC) (RMM, MDC, MS).

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Authors and Affiliations

  1. Department of Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, 19107, PA, USA

    John P Russell, Shogo Shinohara & Jay L Rothstein

  2. Centro di Endocrinologia ed Oncologia Sperimentale del CNR,Dipartimento di Biologia e Patologia. Cellulare e Molecolare, Facolta di Medicina e Chirurgia, Universita di Napoli ‘Federico II,’ S. Pansini 5, Naples, 80131, Italy

    Rosa M Melillo, Maria D Castellone & Massimo Santoro

  3. Department of Otolaryngology-Head and Neck Surgery, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, 19107, PA, USA

    Jay L Rothstein

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  1. John P Russell
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Correspondence to Jay L Rothstein.

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Russell, J., Shinohara, S., Melillo, R. et al. Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors. Oncogene 22, 4569–4577 (2003). https://doi.org/10.1038/sj.onc.1206759

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