| First Author | Neely RJ | Year | 2011 |
| Journal | Oncogene | Volume | 30 |
| Issue | 1 | Pages | 87-96 |
| PubMed ID | 20818435 | Mgi Jnum | J:173147 |
| Mgi Id | MGI:5009780 | Doi | 10.1038/onc.2010.396 |
| Citation | Neely RJ, et al. (2011) The RET/PTC3 oncogene activates classical NF-kappaB by stabilizing NIK. Oncogene 30(1):87-96 |
| abstractText | The oncogenic fusion protein RET/PTC3 (RP3) that is expressed in papillary thyroid carcinoma (PTC) and thyroid epithelia in Hashimoto's thyroiditis activates nuclear factor-kappa B (NF-kappaB) and induces pro-inflammatory gene expression; however, the mechanism of this activation is unknown. To address this, we expressed RP3 in murine embryonic fibroblasts (MEFs) lacking key classical and noncanonical NF-kappaB signaling components. In wild-type MEFs, RP3 upregulated CCL2, CXCL1, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor expression and activated classical but not noncanonical NF-kappaB. RP3-activated NF-kappaB in IkappaB kinase (IKK)beta(-/-) MEFs but not IKKalpha- or NF-kappaB essential modulator (NEMO)-deficient cells and activation was inhibited by a peptide that blocks NEMO binding to the IKKs. RP3 increased the levels of NF-kappaB-inducing kinase (NIK) and did not activate NF-kappaB in NIK-deficient MEFs. Notably, NIK stabilization was not accompanied by TRAF3 degradation demonstrating that RP3 disrupts normal basal NIK regulation. Dominant-negative NIK blocked RP3-induced NF-kappaB activation and an RP3 signaling mutant (RP3(Y588F)) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-kappaB via NIK, NEMO and IKKalpha. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-kappaB activation via stabilization of NIK. |
