Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice

Immunity. 1999 Apr;10(4):421-9. doi: 10.1016/s1074-7613(00)80042-4.

Abstract

IkappaB kinase-alpha and -beta (IKK-alpha and IKK-beta), the catalytic subunits of the IKK complex, phosphorylate IkappaB proteins on specific serine residues, thus targeting IkappaB for degradation and activating the transcription factor NF-kappaB. To elucidate the in vivo function of IKK-beta, we generated IKK-beta-deficient mice. The homozygous mouse embryo dies at approximately 14.5 days of gestation due to liver degeneration and apoptosis. IKK-beta-deficient embryonic fibroblasts have both reduced basal NF-kappaB activity and impaired cytokine-induced NF-kappaB activation. Similarly, basal and cytokine-inducible kinase activities of the IKK complex are greatly reduced in IKK-beta-deficient cells. These results indicate that IKK-beta is crucial for liver development and regulation of NF-kappaB activity and that IKK-alpha can only partially compensate for the loss of IKK-beta.

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line
  • Crosses, Genetic
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Female
  • Fetal Death / enzymology
  • Fetal Death / genetics
  • Fetal Death / immunology*
  • Humans
  • I-kappa B Kinase
  • Interleukin-6 / biosynthesis
  • JNK Mitogen-Activated Protein Kinases
  • Liver / embryology*
  • Liver / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases*
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics*
  • Transfection / immunology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Interleukin-6
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases