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Mol Cell Biol, May 1998, p. 2596-2607, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Alternative Splicing Variants of Ikappa Bbeta Establish Differential NF-kappa B Signal Responsiveness in Human Cells

Fuminori Hirano,1,dagger Mirra Chung,2 Hirotoshi Tanaka,3 Naoki Maruyama,3 Isao Makino,3 David D. Moore,2 and Claus Scheidereit1,*

Max-Delbrück-Center for Molecular Medicine MDC, 13122 Berlin, Germany1; Department of Cell Biology, Baylor College of Medicine, Houston, Texas 770302; and Second Department of Internal Medicine, Asahikawa Medical College, 078 Asahikawa, Japan3

Received 25 August 1997/Returned for modification 17 October 1997/Accepted 29 January 1998

To release transcription factor NF-kappa B into the nucleus, the mammalian Ikappa B molecules Ikappa Balpha and Ikappa Bbeta are inactivated by phosphorylation and proteolytic degradation. Both proteins contain conserved signal-responsive phosphorylation sites and have conserved ankyrin repeats. To confer specific physiological functions to members of the NF-kappa B/Rel family, the different Ikappa B molecules could vary in their specific NF-kappa B/Rel factor binding activities and could respond differently to activation signals. We have demonstrated that both mechanisms apply to differential regulation of NF-kappa B function by Ikappa Bbeta relative to Ikappa Balpha . Via alternative RNA processing, human Ikappa Bbeta gives rise to different protein isoforms. Ikappa Bbeta 1 and Ikappa Bbeta 2, the major forms in human cells, differ in their carboxy-terminal PEST sequences. Ikappa Bbeta 2 is the most abundant species in a number of human cell lines tested, whereas Ikappa Bbeta 1 is the only form detected in murine cells. These isoforms are indistinguishable in their binding preferences to cellular NF-kappa B/Rel homo- and heterodimers, which are distinct from those of Ikappa Balpha , and both are constitutively phosphorylated. In unstimulated B cells, however, Ikappa Bbeta 1, but not Ikappa Bbeta 2, is found in the nucleus. Furthermore, the two forms differ markedly in their efficiency of proteolytic degradation after stimulation with several inducing agents tested. While Ikappa Bbeta 1 is nearly as responsive as Ikappa Balpha , indicative of a shared activation mechanism, Ikappa Bbeta 2 is only weakly degraded and often not responsive at all. Alternative splicing of the Ikappa Bbeta pre-mRNA may thus provide a means to selectively control the amount of Ikappa Bbeta -bound NF-kappa B heteromers to be released under NF-kappa B stimulating conditions.

* Corresponding author. Mailing address: Max-Delbrück-Center for Molecular Medicine MDC, Robert-Rössle-Str. 10, 13122 Berlin, Germany. Phone: 49-30-9406-3816. Fax: 49-30-9406-3866. E-mail: scheidereit{at}mdc-berlin.de.

dagger Present address: Second Department of Internal Medicine, Asahikawa Medical College, Nishikagura 4-5-3, 078 Asahikawa, Japan.

Mol Cell Biol, May 1998, p. 2596-2607, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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