title: Atypical mechanism of NF-κB activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis.
abstract: The NF-κB transcription factor has a central role in diverse processes, including inflammation, proliferation and cell survival, and its activity is dysregulated in diseases such as autoimmunity and cancer. We recently identified the TRE17/ubiquitin-specific protease 6 (USP6) oncogene as the first de-ubiquitinating enzyme to activate NF-κB. TRE17/USP6 is translocated and overexpressed in aneurysmal bone cyst (ABC), a pediatric tumor characterized by extensive bone degradation and inflammatory recruitment. In the current study, we explore the mechanism by which TRE17 induces activation of NF-κB, and find that it activates the classical NF-κB pathway through an atypical mechanism that does not involve IκB degradation. TRE17 co-precipitates with IκB kinase (IKK), and IKK activity is augmented in stable cell lines overexpressing TRE17, in a USP-dependent manner. Optimal activation of NF-κB by TRE17 requires both catalytic subunits of IKK, distinguishing its mechanism from the classical and non-canonical pathways, which require either IKKβ or IKKα, respectively. TRE17 stimulates phosphorylation of p65 at serine 536, a modification that has been associated with enhanced transcriptional activity and nuclear retention. Induction of S536 phosphorylation by TRE17 requires both IKKα and IKKβ, as well as the IKKγ/NEMO regulatory subunit of IKK. We further demonstrate that TRE17(long) is highly tumorigenic when overexpressed in NIH3T3 fibroblasts, and that inhibition of NF-κB significantly attenuates tumor formation. In summary, these studies uncover an unexpected signaling mechanism for activation of classical NF-κB by TRE17. They further reveal a critical role for NF-κB in TRE17-mediated tumorigenesis, and suggest that NF-κB inhibitors may function as effective therapeutic agents in the treatment of ABC.
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Pringle
authors.forename: R
authors.initials: R
authors.lastname: Young
authors.forename: L
authors.initials: L
authors.lastname: Quick
authors.forename: D N
authors.initials: DN
authors.lastname: Riquelme
authors.forename: A M
authors.initials: AM
authors.lastname: Oliveira
authors.forename: M J
authors.initials: MJ
authors.lastname: May
authors.forename: M M
authors.initials: MM
authors.lastname: Chou
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: C501943:IkappaBgamma protein, human; D016328:NF-kappa B; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D012694:Serine; D051550:I-kappa B Kinase; C473330:USP6 protein, human; D043222:Ubiquitin Thiolesterase
references.citation: Oncogene. 1992 Apr;7(4):733-41
references.pmid: 1565468
references.citation: Mol Endocrinol. 2007 Sep;21(9):2203-17
references.pmid: 17595324
references.citation: Clin Cancer Res. 2008 Sep 15;14(18):5656-62
references.pmid: 18794072
references.citation: Trends Biochem Sci. 2005 Jan;30(1):43-52
references.pmid: 15653325
references.citation: Mol Cell Biol. 2003 Mar;23(6):2151-61
references.pmid: 12612085
references.citation: J Immunol. 2003 Jun 1;170(11):5630-5
references.pmid: 12759443
references.citation: Nature. 2003 Aug 14;424(6950):797-801
references.pmid: 12917690
references.citation: Arch Orthop Trauma Surg. 2008 Oct;128(10):1145-7
references.pmid: 17922280
references.citation: Sci STKE. 2006 Oct 17;2006(357):re13
references.pmid: 17047224
references.citation: Arch Orthop Trauma Surg. 2007 Feb;127(2):105-14
references.pmid: 16937137
references.citation: J Biol Chem. 2010 Nov 19;285(47):37111-20
references.pmid: 20864534
references.citation: Cancer Res. 2004 Mar 15;64(6):1920-3
references.pmid: 15026324
references.citation: Oncogene. 2005 May 12;24(21):3419-26
references.pmid: 15735689
references.citation: Annu Rev Biochem. 2009;78:769-96
references.pmid: 19489733
references.citation: Cell Signal. 2009 Oct;21(10):1488-94
references.pmid: 19465115
references.citation: J Immunol. 2004 May 15;172(10):6336-44
references.pmid: 15128824
references.citation: J Biol Chem. 1999 Oct 22;274(43):30353-6
references.pmid: 10521409
references.citation: Trends Mol Med. 2002 Aug;8(8):385-9
references.pmid: 12127724
references.citation: J Biol Chem. 2006 May 12;281(19):13275-13284
references.pmid: 16513650
references.citation: Oncogene. 2006 Oct 30;25(51):6680-4
references.pmid: 17072321
references.citation: J Biol Chem. 2004 Dec 31;279(53):55633-43
references.pmid: 15489227
references.citation: Carcinogenesis. 2004 Oct;25(10):1991-2003
references.pmid: 15192014
references.citation: Oncogene. 2010 Jun 24;29(25):3619-29
references.pmid: 20418905
references.citation: J Immunol. 2004 Dec 1;173(11):6965-72
references.pmid: 15557193
references.citation: Am J Clin Oncol. 2006 Jun;29(3):311-5
references.pmid: 16755186
references.citation: Mol Cell Biol. 2008 Aug;28(16):5061-70
references.pmid: 18541671
references.citation: Cell Res. 2011 Jan;21(1):6-21
references.pmid: 21135871
references.citation: Nature. 2003 Aug 14;424(6950):801-5
references.pmid: 12917691
references.citation: Oncogene. 1999 Nov 22;18(49):6853-66
references.pmid: 10602461
references.citation: Curr Cancer Drug Targets. 2005 Aug;5(5):325-44
references.pmid: 16101381
references.citation: Mol Cell Biol. 2004 Nov;24(22):9752-62
references.pmid: 15509780
references.citation: Nature. 2004 Aug 5;430(7000):694-9
references.pmid: 15258597
references.citation: Nature. 2003 Aug 14;424(6950):793-6
references.pmid: 12917689
references.citation: Mol Cell Biol. 2006 Jan;26(2):457-71
references.pmid: 16382138
references.citation: Am J Pathol. 2004 Nov;165(5):1773-80
references.pmid: 15509545
references.citation: J Virol. 2007 Feb;81(3):1360-71
references.pmid: 17121808
references.citation: Eur J Cancer. 2006 Apr;42(6):760-7
references.pmid: 16510278
references.citation: J Biol Chem. 2007 Mar 23;282(12):8724-33
references.pmid: 17244613
references.citation: J Biol Chem. 2010 Apr 23;285(17):12536-42
references.pmid: 20164172
references.citation: Nature. 2006 May 25;441(7092):431-6
references.pmid: 16724054
references.citation: Mol Cell Biol. 1995 May;15(5):2809-18
references.pmid: 7739562
references.citation: J Clin Oncol. 2005 Sep 20;23(27):6756-62
references.pmid: 16170183
references.citation: J Biol Chem. 2003 Sep 19;278(38):36916-23
references.pmid: 12842894
references.citation: J Biol Chem. 2005 Oct 14;280(41):34538-47
references.pmid: 16105840
references.citation: J Biol Chem. 2002 Feb 8;277(6):3863-9
references.pmid: 11733537
references.citation: Cell Res. 2011 Jan;21(1):22-39
references.pmid: 21119682
references.citation: J Biol Chem. 2005 Oct 28;280(43):35967-73
references.pmid: 16127172
references.citation: Curr Med Chem. 2007;14(3):367-76
references.pmid: 17305539