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PMID: 10990461 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription.

The EMBO journal ·Vol. 19 ·No. 18 ·2000-09-15 ·Pages 4976-85

Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itié A, Wakeham A, Shahinian A, Henzel WJ, Elia AJ, Shillinglaw W, Mak TW, Cao Z, Yeh WC

Abstract

Induction of NF-kappaB-dependent transcription requires phosphorylation and subsequent degradation of I-kappaB, an inhibitor of NF-kappaB, followed by nuclear translocation and DNA binding of NF-kappaB. Tumor necrosis factor receptor-associated factor 2 (TRAF2) plays a role in NF-kappaB activation in response to cytokines such as tumor necrosis factor alpha (TNFalpha). 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-kappaBalpha in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2k(-/-) animals die at approximately E14.5 of massive liver degeneration and apoptosis. Never theless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNFalpha-induced apoptosis. In response to either TNFalpha or IL-1 induction, t2k(-/-) embryonic fibroblasts exhibit normal degradation of I-kappaB and kappaB-binding activity. However, NF-kappaB-directed transcription is dramatically reduced. These results demonstrate that, like I-kappaB kinase beta and the RelA subunit of NF-kappaB, T2K is critical in protecting embryonic liver from apoptosis. However, T2K has a unique role in the activation of NF-kappaB-directed transcription, apparently independent of I-kappaB degradation and NF-kappaB DNA binding.

MeSH Terms
Amino Acid Sequence Animals Apoptosis Blotting, Southern Cycloheximide/pharmacology Dose-Response Relationship, Drug Female Fibroblasts/metabolism Flow Cytometry Gene Targeting Genes, Reporter Genotype Heterozygote I-kappa B Kinase In Situ Nick-End Labeling Interleukin-1/pharmacology Ligases/metabolism Liver/metabolism,pathology Lymphocytes/metabolism Male Mice Mice, Inbred C57BL Mice, Transgenic Models, Genetic Molecular Sequence Data NF-kappa B/biosynthesis,genetics Phosphorylation Precipitin Tests Protein Binding Protein Serine-Threonine Kinases/metabolism,physiology Protein Synthesis Inhibitors/pharmacology Proteins/metabolism Recombinant Proteins/metabolism TNF Receptor-Associated Factor 2 Thymus Gland/cytology Time Factors Transcription, Genetic Tumor Necrosis Factor-alpha/metabolism
Chemicals
Interleukin-1 NF-kappa B Protein Synthesis Inhibitors Proteins Recombinant Proteins TNF Receptor-Associated Factor 2 Tumor Necrosis Factor-alpha Cycloheximide Tbk1 protein, mouse Protein Serine-Threonine Kinases Chuk protein, mouse I-kappa B Kinase Ikbkb protein, mouse Ikbke protein, mouse Ligases guanosine 3',5'-polyphosphate synthetases
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Bonnard M
Amgen Institute, Ontario Cancer Institute and the Department of Medical Biophysics, University of Toronto, 620 University Avenue, Toronto, Ontario, Canada.
Mirtsos C
Suzuki S
Graham K
Huang J
Ng M
Itié A
Wakeham A
Shahinian A
Henzel W J
Elia A J
Shillinglaw W
Mak T W
Cao Z
Yeh W C
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.18.4976
Published
2000-09-15
Pages
4976-85
Language
English
Region
England
NLM ID
8208664
PMCID
PMC314216
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/19.18.4976 PMC Full Text View journal details
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