The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/10/999/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 7, October 6, 1997 999-1014

Articles

Gastric Hyperplasia and Increased Proliferative Responses of Lymphocytes in Mice Lacking the COOH-terminal Ankyrin Domain of NF-{kappa}B2

Hideaki Ishikawa, Daniel Carrasco, Estefania Claudio, Rolf-Peter Ryseck, and Rodrigo Bravo

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-{kappa}B, the p100 precursor is believed to function as an inhibitor of Rel/NF-{kappa}B activity by cytoplasmic retention of Rel/NF-{kappa}B complexes, like other members of the I{kappa}B family. However, the physiological relevance of the p100 precursor as an I{kappa}B 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-{kappa}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 {kappa}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-{kappa}B complexes in various cell types and its absence cannot be efficiently compensated for by other I{kappa}B proteins.

Address correspondence to Dr. Rodrigo Bravo, Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543. Phone: 609-252-5744; FAX: 609-252-6051.

1 Abbreviations used in this paper: EGF, epidermal growth factor; EMSA, electrophoretic mobility shift assay; ES, embryonic stem; NLS, nuclear localization signal; P, postnatal day(s); PGK, phosphoglycerate kinase; RT, reverse transcriptase; VCAM-1, vascular adhesion molecule 1.


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