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Science 9 April 1999:
Vol. 284. no. 5412, pp. 321 - 325
DOI: 10.1126/science.284.5412.321
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Reports

Severe Liver Degeneration in Mice Lacking the Ikappa B Kinase 2 Gene

Qiutang Li, 1 Daniel Van Antwerp, 1 Frank Mercurio, 2 Kuo-Fen Lee, 1 Inder M. Verma 1*

Phosphorylation of inhibitor of kappa B (Ikappa B) proteins is an important step in the activation of the transcription nuclear factor kappa B (NF-kappa B) and requires two Ikappa B kinases, IKK1 (IKKalpha ) and IKK2 (IKKbeta ). Mice that are devoid of the IKK2 gene had extensive liver damage from apoptosis and died as embryos, but these mice could be rescued by the inactivation of the gene encoding tumor necrosis factor receptor 1. Mouse embryonic fibroblast cells that were isolated from IKK2-/- embryos showed a marked reduction in tumor necrosis factor-alpha (TNF-alpha )- and interleukin-1alpha -induced NF-kappa B activity and an enhanced apoptosis in response to TNF-alpha . IKK1 associated with NF-kappa B essential modulator (IKKgamma /IKKAP1), another component of the IKK complex. These results show that IKK2 is essential for mouse development and cannot be substituted with IKK1.

1 Salk Institute, La Jolla, CA 92037, USA.
2 Signal Pharmaceuticals, San Diego, CA 92121, USA.
*   To whom correspondence should be addressed. E-mail: verma{at}salk.edu

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NAK Is Recruited to the TNFR1 Complex in a TNF{alpha}-dependent Manner and Mediates the Production of RANTES: IDENTIFICATION OF ENDOGENOUS TNFR-INTERACTING PROTEINS BY A PROTEOMIC APPROACH.
J. Kuai, J. Wooters, J. P. Hall, V. R. Rao, E. Nickbarg, B. Li, M. Chatterjee-Kishore, Y. Qiu, and L.-L. Lin (2004)
J. Biol. Chem. 279, 53266-53271
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Efficient Replication by Herpes Simplex Virus Type 1 Involves Activation of the I{kappa}B Kinase-I{kappa}B-p65 Pathway.
D. Gregory, D. Hargett, D. Holmes, E. Money, and S. L. Bachenheimer (2004)
J. Virol. 78, 13582-13590
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RhoA/Rho-Associated Kinase Pathway Selectively Regulates Thrombin-Induced Intercellular Adhesion Molecule-1 Expression in Endothelial Cells via Activation of I{kappa}B Kinase {beta} and Phosphorylation of RelA/p65.
K. N. Anwar, F. Fazal, A. B. Malik, and A. Rahman (2004)
J. Immunol. 173, 6965-6972
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Tumor Necrosis Factor Alpha Induction of NF-{kappa}B Requires the Novel Coactivator SIMPL.
H.-J. Kwon, E. H. Breese, E. Vig-Varga, Y. Luo, Y. Lee, M. G. Goebl, and M. A. Harrington (2004)
Mol. Cell. Biol. 24, 9317-9326
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Nuclear factor (NF)-{kappa}B proteins: therapeutic targets.
I M Verma (2004)
Ann Rheum Dis 63, ii57-ii61
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A Novel Ubiquitin-like Domain in I{kappa}B Kinase {beta} Is Required for Functional Activity of the Kinase.
M. J. May, S. E. Larsen, J. H. Shim, L. A. Madge, and S. Ghosh (2004)
J. Biol. Chem. 279, 45528-45539
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Identification of Hypoxia-Regulated Proteins in Head and Neck Cancer by Proteomic and Tissue Array Profiling.
Y. Chen, G. Shi, W. Xia, C. Kong, S. Zhao, A. F. Gaw, E. Y. Chen, G. P. Yang, A. J. Giaccia, Q.-T. Le, et al. (2004)
Cancer Res. 64, 7302-7310
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Regulation of {alpha}-Fetoprotein by Nuclear Factor-{kappa}B Protects Hepatocytes from Tumor Necrosis Factor-{alpha} Cytotoxicity during Fetal Liver Development and Hepatic Oncogenesis.
L. G. Cavin, M. Venkatraman, V. M. Factor, S. Kaur, I. Schroeder, F. Mercurio, A. A. Beg, S. S. Thorgeirsson, and M. Arsura (2004)
Cancer Res. 64, 7030-7038
   Abstract »    Full Text »    PDF »
Signaling to NF-{kappa}B.
M. S. Hayden and S. Ghosh (2004)
Genes & Dev. 18, 2195-2224
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Detection of IKK{beta}-IKK{gamma} Subcomplexes in Monocytic Cells and Characterization of Associated Signaling.
M. Quirling, S. Page, N. Jilg, K. Plenagl, D. Peus, C. Grubmuller, M. Weingartner, C. Fischer, D. Neumeier, and K. Brand (2004)
J. Biol. Chem. 279, 37452-37460
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NF-{kappa}B and AP-1 Connection: Mechanism of NF-{kappa}B-Dependent Regulation of AP-1 Activity.
S. Fujioka, J. Niu, C. Schmidt, G. M. Sclabas, B. Peng, T. Uwagawa, Z. Li, D. B. Evans, J. L. Abbruzzese, and P. J. Chiao (2004)
Mol. Cell. Biol. 24, 7806-7819
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Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of I{kappa}B kinase activity.
S. Bhattacharyya, P. Sen, M. Wallet, B. Long, A. S. Baldwin Jr, and R. Tisch (2004)
Blood 104, 1100-1109
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The Transcription Factors c-rel and RelA Control Epidermal Development and Homeostasis in Embryonic and Adult Skin via Distinct Mechanisms.
R. Gugasyan, A. Voss, G. Varigos, T. Thomas, R. J. Grumont, P. Kaur, G. Grigoriadis, and S. Gerondakis (2004)
Mol. Cell. Biol. 24, 5733-5745
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I{kappa}B Kinase Is an Essential Component of the Tpl2 Signaling Pathway.
M. Waterfield, W. Jin, W. Reiley, M. Zhang, and S.-C. Sun (2004)
Mol. Cell. Biol. 24, 6040-6048
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Stabilization of p53 Is a Novel Mechanism for Proapoptotic Function of NF-{kappa}B.
S. Fujioka, C. Schmidt, G. M. Sclabas, Z. Li, H. Pelicano, B. Peng, A. Yao, J. Niu, W. Zhang, D. B. Evans, et al. (2004)
J. Biol. Chem. 279, 27549-27559
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p53 Induces NF-{kappa}B Activation by an I{kappa}B Kinase-independent Mechanism Involving Phosphorylation of p65 by Ribosomal S6 Kinase 1.
J. Bohuslav, L.-f. Chen, H. Kwon, Y. Mu, and W. C. Greene (2004)
J. Biol. Chem. 279, 26115-26125
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Characterization of NF-{kappa}B/I{kappa}B Proteins in Zebra Fish and Their Involvement in Notochord Development.
R. G. Correa, V. Tergaonkar, J. K. Ng, I. Dubova, J. C. Izpisua-Belmonte, and I. M. Verma (2004)
Mol. Cell. Biol. 24, 5257-5268
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Combined deficiency in I{kappa}B{alpha} and I{kappa}B{epsilon} reveals a critical window of NF-{kappa}B activity in natural killer cell differentiation.
S. I. Samson, S. Memet, C. A. J. Vosshenrich, F. Colucci, O. Richard, D. Ndiaye, A. Israel, and J. P. Di Santo (2004)
Blood 103, 4573-4580
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Inhibitor of {kappa}B kinase is required to activate a subset of interferon {gamma}-stimulated genes.
N. Sizemore, A. Agarwal, K. Das, N. Lerner, M. Sulak, S. Rani, R. Ransohoff, D. Shultz, and G. R. Stark (2004)
PNAS 101, 7994-7998
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Activation of the NF-{kappa}B Pathway in Human Cytomegalovirus-Infected Cells Is Necessary for Efficient Transactivation of the Major Immediate-Early Promoter.
I. B. DeMeritt, L. E. Milford, and A. D. Yurochko (2004)
J. Virol. 78, 4498-4507
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Human T-cell Lymphotropic Virus Type 1 Tax Induction of Biologically Active NF-{kappa}B Requires I{kappa}B Kinase-1-mediated Phosphorylation of RelA/p65.
A. M. O'Mahony, M. Montano, K. Van Beneden, L.-F. Chen, and W. C. Greene (2004)
J. Biol. Chem. 279, 18137-18145
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