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Functional Redundancy of the Nuclear Factor B Inhibitors IB and IBβ

Janet D. Cheng^*, Rolf-Peter Ryseck^*, Ricardo M. Attar^*, Donna Dambach, and Rodrigo Bravo^*

From the ^* Department of Oncology and the Department of Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000

The transcription factor NF-B is sequestered in the cytoplasm by the inhibitor proteins of the IB family. Each member of the IB exhibits structural and biochemical similarities as well as differences. In an effort to address the functional redundancy of two closely related IB molecules, IB and IBβ, we generated knock-in mice by replacing the IB gene with the IBβ gene. The knock-in mice do not express IB, but express a T7-tagged IBβ under the promoter and regulatory sequence of ikba. Unlike the IB-deficient mice, which display severe postnatal developmental defects and die by postnatal day 8, homozygous knock-in mice survive to adulthood, are fertile, and exhibit no apparent abnormalities. Furthermore, thymocytes and embryonic fibroblasts from the knock-in animals exhibit an inducible NF-B response similar to that of wild-type animals. These results indicate that IB and IBβ share significant similarities in their biochemical activity, and that they acquired their different functions from divergent expression patterns during evolution.

Key Words: nuclear factor B • IB • transgenic mice • knockout mice • hematopoiesis

Abbreviations used: EMSA, electrophoretic mobility shift assay; ES, embryonic stem; MEF, mouse embryo fibroblast, NF-B, nuclear factor B.

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