TITLE

Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-?B-dependent gene transcription

AUTHOR(S)
Bonnard, Madeleine; Mirtsos, Christine; Suzuki, Shinobu; Graham, Kevin; Jianing Huang; Ng, Michelle; Itié, Annick; Wakeham, Andrew; Shahinian, Arda; Henzel, William J.; Elia, Andrew J.; Shillinglaw, Wendy; Mak, Tak W.; Cao, Zhaodan; Wen-Chen Yeh
PUB. DATE
September 2000
SOURCE
EMBO Journal;9/15/2000, Vol. 19 Issue 18, p4976
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Induction 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.
ACCESSION #
13005037

 

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