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
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
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DOI：
10.1074/jbc.m111.322677
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发表时间：
2012-02-03
影响因子：
4.8
通讯作者：
Eisenlohr, Laurence C.
中科院分区：
文献类型：
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作者：
Wixted, Josephine H. F.;Rothstein, Jay L.;Eisenlohr, Laurence C.
携带RET/PTC癌基因的甲状腺癌与表达致癌RAS或BRAF突变的甲状腺癌相比是分化良好的相对良性肿瘤，尽管通过共享的转化途径进行信号传导。然而，一个区别是RET/PTC诱导免疫刺激程序，表明在这种肿瘤类型的情况下，额外的促炎途径降低了侵袭性。在这里，我们证明了促炎程序被TRAF 2和TRAF 6与RET/PTC癌蛋白的结合选择性激活。消除这种机制减少了促炎细胞因子的产生，而不降低转化效率。相反，消除MEK/ERK或PI 3 K/AKT信号传导消除转化，但不消除促炎细胞因子分泌。这两种途径的功能解偶联表明，内在的促炎途径不是细胞转化所必需的，并表明需要进一步研究炎症在甲状腺肿瘤进展中的作用。
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.