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Article: Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription

TitleDeficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription
Authors
KeywordsNF-κB
TNF signaling
Apoptosis
T2K
I-κB kinase
Issue Date2000
Citation
EMBO Journal, 2000, v. 19, n. 18, p. 4976-4985 How to Cite?
AbstractInduction of NF-κB-dependent transcription requires phosphorylation and subsequent degradation of I-κB, an inhibitor of NF-κB, followed by nuclear translocation and DNA binding of NF-κB. Tumor necrosis factor receptor-associated factor 2 (TRAF2) plays a role in NF-κB activation in response to cytokines such as tumor necrosis factor α (TNFα). In this study, we purified and characterized a novel kinase (T2K, also known as TBK1 or NAK), which associates with TRAF2 and exhibits kinase activity towards I-κBα in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2k(-/-) animals die at ~E14.5 of massive liver degeneration and apoptosis. Nevertheless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNFα-induced apoptosis. In response to either TNFα or IL-1 induction, t2k(-/-) embryonic fibroblasts exhibit normal degradation of I-κB and κB-binding activity. However, NF-κB-directed transcription is dramatically reduced. These results demonstrate that, like I-κB kinase β and the RelA subunit of NF-κB, T2K is critical in protecting embryonic liver from apoptosis. However, T2K has a unique role in the activation of NF-κB-directed transcription, apparently independent of I-κB degradation and NF-κB DNA binding.
Persistent Identifierhttp://hdl.handle.net/10722/291541
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 5.489
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorBonnard, Madeleine-
dc.contributor.authorMirtsos, Christine-
dc.contributor.authorSuzuki, Shinobu-
dc.contributor.authorGraham, Kevin-
dc.contributor.authorHuang, Jianing-
dc.contributor.authorNg, Michelle-
dc.contributor.authorItié, Annick-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorShahinian, Arda-
dc.contributor.authorHenzel, William J.-
dc.contributor.authorElia, Andrew J.-
dc.contributor.authorShillinglaw, Wendy-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorCao, Zhaodan-
dc.contributor.authorYeh, Wen Chen-
dc.date.accessioned2020-11-17T14:54:35Z-
dc.date.available2020-11-17T14:54:35Z-
dc.date.issued2000-
dc.identifier.citationEMBO Journal, 2000, v. 19, n. 18, p. 4976-4985-
dc.identifier.issn0261-4189-
dc.identifier.urihttp://hdl.handle.net/10722/291541-
dc.description.abstractInduction of NF-κB-dependent transcription requires phosphorylation and subsequent degradation of I-κB, an inhibitor of NF-κB, followed by nuclear translocation and DNA binding of NF-κB. Tumor necrosis factor receptor-associated factor 2 (TRAF2) plays a role in NF-κB activation in response to cytokines such as tumor necrosis factor α (TNFα). In this study, we purified and characterized a novel kinase (T2K, also known as TBK1 or NAK), which associates with TRAF2 and exhibits kinase activity towards I-κBα in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2k(-/-) animals die at ~E14.5 of massive liver degeneration and apoptosis. Nevertheless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNFα-induced apoptosis. In response to either TNFα or IL-1 induction, t2k(-/-) embryonic fibroblasts exhibit normal degradation of I-κB and κB-binding activity. However, NF-κB-directed transcription is dramatically reduced. These results demonstrate that, like I-κB kinase β and the RelA subunit of NF-κB, T2K is critical in protecting embryonic liver from apoptosis. However, T2K has a unique role in the activation of NF-κB-directed transcription, apparently independent of I-κB degradation and NF-κB DNA binding.-
dc.languageeng-
dc.relation.ispartofEMBO Journal-
dc.subjectNF-κB-
dc.subjectTNF signaling-
dc.subjectApoptosis-
dc.subjectT2K-
dc.subjectI-κB kinase-
dc.titleDeficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1093/emboj/19.18.4976-
dc.identifier.pmid10990461-
dc.identifier.pmcidPMC314216-
dc.identifier.scopuseid_2-s2.0-0034665047-
dc.identifier.volume19-
dc.identifier.issue18-
dc.identifier.spage4976-
dc.identifier.epage4985-
dc.identifier.isiWOS:000089569100012-
dc.identifier.issnl0261-4189-

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