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J. Exp. Med.,
Volume 189, Number 11, June 7, 1999 1839-1845
Subunit of I
B Kinase (IKK) is Essential for
Nuclear Factor B Activation and Prevention of Apoptosis
By
From the * Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, The I Department of Biology, and § Department of Neuroscience, University of California, San Diego,
La Jolla, California 92093-0636
B kinase (IKK) complex is composed of three subunits, IKK
, IKK
, and IKK
(NEMO). While IKK and IKK are highly similar catalytic subunits, both capable of IB
phosphorylation in vitro, IKK is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKK and
IKK have distinct functions. Surprisingly, disruption of the Ikk locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor
(NF)-B activation. Now we describe the pathophysiological consequence of disruption of the
Ikk locus. IKK-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-B1
(p50/p105) subunits of NF-B. Accordingly, IKK-deficient cells are defective in activation of
IKK and NF-B in response to either tumor necrosis factor or interleukin 1. Thus IKK,
but not IKK, plays the major role in IKK activation and induction of NF-B activity. In the
absence of IKK, IKK is unresponsive to IKK activators.
;
interleukin 1;
knockout mice;
signal transduction
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