title: Identification of functionally distinct TRAF proinflammatory and phosphatidylinositol 3-kinase/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (PI3K/MEK) transforming activities emanating from RET/PTC fusion oncoprotein.
abstract: Thyroid carcinomas that harbor RET/PTC oncogenes are well differentiated, relatively benign neoplasms compared with those expressing oncogenic RAS or BRAF mutations despite signaling through shared transforming pathways. A distinction, however, is that RET/PTCs induce immunostimulatory programs, suggesting that, in the case of this tumor type, the additional pro-inflammatory pathway reduces aggressiveness. Here, we demonstrate that pro-inflammatory programs are selectively activated by TRAF2 and TRAF6 association with RET/PTC oncoproteins. Eliminating this mechanism reduces pro-inflammatory cytokine production without decreasing transformation efficiency. Conversely, ablating MEK/ERK or PI3K/AKT signaling eliminates transformation but not pro-inflammatory cytokine secretion. Functional uncoupling of the two pathways demonstrates that intrinsic pro-inflammatory pathways are not required for cellular transformation and suggests a need for further investigation into the role inflammation plays in thyroid tumor progression.
authors.affiliation: Immunology and Microbial Pathogenesis Program, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Josephine H F
authors.initials: JH
authors.lastname: Wixted
authors.forename: Jay L
authors.initials: JL
authors.lastname: Rothstein
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Eisenlohr
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D015514:Oncogene Proteins, Fusion; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C490558:RET-PTC oncoprotein, rat; C093573:ret-PTC fusion oncoproteins, human; D020929:Mitogen-Activated Protein Kinase Kinases