The RET/PTC3 oncogene activates classical NF-B by stabilizing NIK

R. J. Neely, M. S. Brose, C. M. Gray, K. A. McCorkell, J. M. Leibowitz, C. Ma, J. L. Rothstein, M. J. May

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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-B) 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-B 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-κB. RP3-activated NF-κB in IB kinase (IKK)Β / MEFs but not IKKα- or NF-κB 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-κB-inducing kinase (NIK) and did not activate NF-κB 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-κB 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-κB via NIK, NEMO and IKKα. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-κB activation via stabilization of NIK.

Original languageEnglish (US)
Pages (from-to)87-96
Number of pages10
JournalOncogene
Volume30
Issue number1
DOIs
StatePublished - Jan 6 2011
Externally publishedYes

Keywords

  • Hashimoto's thyroiditis
  • IKK
  • NF-κB
  • NIK
  • RET/PTC
  • thyroid cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Neely, R. J., Brose, M. S., Gray, C. M., McCorkell, K. A., Leibowitz, J. M., Ma, C., Rothstein, J. L., & May, M. J. (2011). The RET/PTC3 oncogene activates classical NF-B by stabilizing NIK. Oncogene, 30(1), 87-96. https://doi.org/10.1038/onc.2010.396