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Updated: Jun 9, 2026
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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
Published on: November 2, 2018
The RET/PTC3 oncogene activates classical NF-κB by stabilizing NIK.
R J Neely1, M S Brose, C M Gray
1Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
Oncogene
|September 7, 2010
Summary
The RET/PTC3 fusion protein activates nuclear factor-kappa B (NF-κB) signaling in thyroid cancer by stabilizing NF-κB-inducing kinase (NIK). This discovery reveals a new oncogene-driven mechanism for NF-κB activation.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- The RET/PTC3 (RP3) fusion protein, found in papillary thyroid carcinoma (PTC), activates nuclear factor-kappa B (NF-κB) and pro-inflammatory gene expression.
- The precise mechanism by which RP3 activates NF-κB remains unclear.
Purpose of the Study:
- To elucidate the mechanism of RP3-mediated NF-κB activation.
- To investigate the role of NF-κB signaling components in RP3-induced inflammation.
Main Methods:
- RP3 was expressed in murine embryonic fibroblasts (MEFs) deficient in key NF-κB signaling molecules.
- NF-κB activation, gene expression, and protein levels (NIK, TRAF3) were analyzed.
- Inhibition studies using a NEMO-binding peptide and dominant-negative NIK were performed.
- PTC specimens were examined for NIK expression.
Main Results:
- RP3 upregulated pro-inflammatory genes (CCL2, CXCL1, GM-CSF, TNF) and activated classical NF-κB in wild-type MEFs.
- Activation occurred in IKKβ(-/-) MEFs but not in IKKα- or NEMO-deficient cells.
- RP3 increased NIK levels and failed to activate NF-κB in NIK-deficient MEFs.
- RP3-induced NF-κB activation was blocked by dominant-negative NIK and required NEMO and IKKα.
- NIK stabilization by RP3 occurred independently of TRAF3 degradation.
- PTC samples showed strong NIK staining.
Conclusions:
- RP3 activates classical NF-κB through a pathway involving NIK, NEMO, and IKKα.
- This study reveals a novel mechanism of oncogene-induced NF-κB activation mediated by NIK stabilization.
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