The RET/PTC3 oncogene activates classical NF-[kappa]B by stabilizing NIK
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-[kappa]B) and induces pro-inflammatory gene expression; however, the mechanism of this activation is unknown....
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creator | Neely, R J Brose, M S Gray, C M Mccorkell, K A Leibowitz, J M Ma, C Rothstein, J L May, M J |
description | 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-[kappa]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-[kappa]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-[kappa]B. RP3-activated NF-[kappa]B in I[kappa]B kinase (IKK)[beta]-/- MEFs but not IKK[alpha]- or NF-[kappa]B 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-[kappa]B-inducing kinase (NIK) and did not activate NF-[kappa]B 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-[kappa]B activation and an RP3 signaling mutant (RP3Y588F) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-[kappa]B via NIK, NEMO and IKK[alpha]. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-[kappa]B activation via stabilization of NIK. [PUBLICATION ABSTRACT] |
doi_str_mv | 10.1038/onc.2010.396 |
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To address this, we expressed RP3 in murine embryonic fibroblasts (MEFs) lacking key classical and noncanonical NF-[kappa]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-[kappa]B. RP3-activated NF-[kappa]B in I[kappa]B kinase (IKK)[beta]-/- MEFs but not IKK[alpha]- or NF-[kappa]B 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-[kappa]B-inducing kinase (NIK) and did not activate NF-[kappa]B 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-[kappa]B activation and an RP3 signaling mutant (RP3Y588F) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-[kappa]B via NIK, NEMO and IKK[alpha]. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-[kappa]B activation via stabilization of NIK. [PUBLICATION ABSTRACT]</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2010.396</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>New York: Nature Publishing Group</publisher><subject>Cellular biology ; Gene expression ; Oncology ; Rodents ; Thyroid diseases</subject><ispartof>Oncogene, 2011-01, Vol.30 (1), p.87</ispartof><rights>Copyright Nature Publishing Group Jan 6, 2011</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Neely, R J</creatorcontrib><creatorcontrib>Brose, M S</creatorcontrib><creatorcontrib>Gray, C M</creatorcontrib><creatorcontrib>Mccorkell, K A</creatorcontrib><creatorcontrib>Leibowitz, J M</creatorcontrib><creatorcontrib>Ma, C</creatorcontrib><creatorcontrib>Rothstein, J L</creatorcontrib><creatorcontrib>May, M J</creatorcontrib><title>The RET/PTC3 oncogene activates classical NF-[kappa]B by stabilizing NIK</title><title>Oncogene</title><description>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-[kappa]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-[kappa]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-[kappa]B. RP3-activated NF-[kappa]B in I[kappa]B kinase (IKK)[beta]-/- MEFs but not IKK[alpha]- or NF-[kappa]B 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-[kappa]B-inducing kinase (NIK) and did not activate NF-[kappa]B 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-[kappa]B activation and an RP3 signaling mutant (RP3Y588F) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-[kappa]B via NIK, NEMO and IKK[alpha]. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-[kappa]B activation via stabilization of NIK. 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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-[kappa]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-[kappa]B. RP3-activated NF-[kappa]B in I[kappa]B kinase (IKK)[beta]-/- MEFs but not IKK[alpha]- or NF-[kappa]B 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-[kappa]B-inducing kinase (NIK) and did not activate NF-[kappa]B 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-[kappa]B activation and an RP3 signaling mutant (RP3Y588F) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-[kappa]B via NIK, NEMO and IKK[alpha]. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-[kappa]B activation via stabilization of NIK. [PUBLICATION ABSTRACT]</abstract><cop>New York</cop><pub>Nature Publishing Group</pub><doi>10.1038/onc.2010.396</doi></addata></record> |
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title | The RET/PTC3 oncogene activates classical NF-[kappa]B by stabilizing NIK |
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