Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors.
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-kappaB 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.
Russell
John P
JP
Department of Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Shinohara
Shogo
S
Melillo
Rosa M
RM
Castellone
Maria D
MD
Santoro
Massimo
M
Rothstein
Jay L
JL
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002630:Chemotactic Factors / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D014157:Transcription Factors
D018932:Chemokine CCL2; D002630:Chemotactic Factors; D016207:Cytokines; C111382:NCOA4 protein, human; D016328:NF-kappa B; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases