Severe Liver Degeneration in Mice Lacking the IκB Kinase 2 Gene

  title={Severe Liver Degeneration in Mice Lacking the I$\kappa$B Kinase 2 Gene},
  author={Qiutang Li and Daniel J. van Antwerp and Frank Mercurio and Kuo-Fen Lee and Inder M. Verma},
Phosphorylation of inhibitor of kappa B (IκB) proteins is an important step in the activation of the transcription nuclear factor kappa B (NF-κB) and requires two IκB kinases, IKK1 (IKKα) and IKK2 (IKKβ). 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… 

Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice.

In vivo evidence is provided that NEMO/IKKgamma is the first essential, noncatalytic component of the IKK complex, and mutant MEFs show increased sensitivity to TNFalpha-induced apoptosis.

Severe liver degeneration and lack of NF - k B activation in NEMO/IKK g -deficient mice

In vivo evidence is provided that NEMO/IKK g is the first essential, noncatalytic component of the IKK complex, and mutant MEFs show increased sensitivity to TNF a -induced apoptosis.

Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury.

AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.

I-κB Kinases α and β Have Distinct Roles in Regulating Murine T Cell Function1

It is demonstrated that IKKα and IKKβ have opposite roles on the regulation of anti-CD3-induced apoptosis of double-positive thymocytes, suggesting that IKR and IKR have distinct roles in regulating thymocyte function.

Iκb Kinase α Is Essential for Mature B Cell Development and Function

Results demonstrate that IKKα is critically involved in the prevention of cell death and functional development of mature B cells and transgene expression of bcl-2 could only partially rescue impaired B cell development in IKK α−/− chimeras.

TAB2 Is Essential for Prevention of Apoptosis in Fetal Liver but Not for Interleukin-1 Signaling

It is demonstrated that TAB2 is essential for embryonic development through prevention of liver apoptosis but not for the IL-1 receptor-mediated signaling pathway.

Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR-1 double knockout mice.

IκB Kinase Signaling Is Essential for Maintenance of Mature B Cells

It is concluded that maintenance of mature B cells depends on IKK-mediated activation of NF-κB, and that B lineage–specific disruption of either IKK signaling by deletion of NEMO, or of IKK2-specific signals by ablation of Ikk2 activity leads to the disappearance of maturity B lymphocytes.

Inactivation of BAD by IKK Inhibits TNFα-Induced Apoptosis Independently of NF-κB Activation




IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation

Activation of the transcription factor nuclear factor kappa B (NF-κB) is controlled by sequential phosphorylation, ubiquitination, and degradation of its inhibitory subunit IκB. A large multiprotein

IKK-γ is an essential regulatory subunit of the IκB kinase complex

By using a monoclonal antibody against IKK-α, the IKK complex is purify to homogeneity from human cell lines and it is found that IKK is composed of similar amounts of IKK, α and β and two other polypeptides, for which the authors obtained partial sequences.

IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK

Overexpression of a catalytically inactive form of IKK-β blocked cytokine-induced NF-κB activation and suggested that an active IκB kinase complex may require three distinct protein kinases.

MEK Kinase Is Involved in Tumor Necrosis Factor α-Induced NF-κB Activation and Degradation of IκB-α*

It is suggested that MEK kinase is a signal mediator involved in TNFα-induced NF-κB activation and that the activation of NF-kkB by MEK Kinase is regulated through the degradation of IκB-α.

Direct Phosphorylation of IκB by IKKα and IKKβ: Discrimination Between Free and NF-κB-Bound Substrate

Purified recombinant IKKα and IKKβ expressed in insect cells were used to demonstrate that each protein can directly phosphorylate IκB proteins, explaining how free IkkB can accumulate in cells in which IKK is still active and thus can contribute to the termination of NF-κB activation.

A cytokine-responsive IκB kinase that activates the transcription factor NF-κB

IKK turns out to be the long-sought-after protein kinase that mediates the critical regulatory step in NF-κB activation, and phosphorylates IκBs on the sites that trigger their degradation.

Suppression of TNF-α-Induced Apoptosis by NF-κB

The sensitivity and kinetics of TNF-α-induced apoptosis are shown to be enhanced in a number of cell types expressing a dominant-negative IκB α (IκBαM).

Function and activation of NF-kappa B in the immune system.

The inhibition of NF-kappa B activation by antioxidants and specific protease inhibitors may provide a pharmacological basis for interfering with these acute processes in suppressing toxic/septic shock, graft-vs-host reactions, acute inflammatory reactions, severe phase response, and radiation damage.