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B2
By
From The Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute,
Princeton, New Jersey 08543-4000
The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic
cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative
subunit of NF-
B, the p100 precursor is believed to function as an inhibitor of Rel/NF-B
activity by cytoplasmic retention of Rel/NF-B complexes, like other members of the IB
family. However, the physiological relevance of the p100 precursor as an IB molecule has not
been understood. To assess the role of the precursor in vivo, we generated, by gene targeting,
mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-B2 (p100
/) had marked gastric hyperplasia, resulting in early postnatal death. p100/ animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in
response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic
induction of nuclear B-binding activity composed of p52-containing complexes was found in
all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential
for the proper regulation of p52-containing Rel/NF-B complexes in various cell types and its
absence cannot be efficiently compensated for by other IB proteins.
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