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Molecular and Cellular Biology, April 1999, p. 2690-2698, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

NF-kappa B Function in Growth Control: Regulation of Cyclin D1 Expression and G0/G1-to-S-Phase Transition

Michael Hinz,1 Daniel Krappmann,2 Alexandra Eichten,1 Andreas Heder,1 Claus Scheidereit,2 and Michael Strauss1,3,*

Molekulare Zellbiologie, Humboldt Universität zu Berlin, Max-Delbrück-Haus,1 and Max-Delbrück-Center for Molecular Medicine,2 13122 Berlin, Germany, and Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark3

Received 27 July 1998/Returned for modification 18 September 1998/Accepted 30 December 1998

Nuclear factor kappa B (NF-kappa B) has been implicated in the regulation of cell proliferation, transformation, and tumor development. We provide evidence for a direct link between NF-kappa B activity and cell cycle regulation. NF-kappa B was found to stimulate transcription of cyclin D1, a key regulator of G1 checkpoint control. Two NF-kappa B binding sites in the human cyclin D1 promoter conferred activation by NF-kappa B as well as by growth factors. Both levels and kinetics of cyclin D1 expression during G1 phase were controlled by NF-kappa B. Moreover, inhibition of NF-kappa B caused a pronounced reduction of serum-induced cyclin D1-associated kinase activity and resulted in delayed phosphorylation of the retinoblastoma protein. Furthermore, NF-kappa B promotes G1-to-S-phase transition in mouse embryonal fibroblasts and in T47D mammary carcinoma cells. Impaired cell cycle progression of T47D cells expressing an NF-kappa B superrepressor (Ikappa Balpha Delta N) could be rescued by ectopic expression of cyclin D1. Thus, NF-kappa B contributes to cell cycle progression, and one of its targets might be cyclin D1.

* Corresponding author. Mailing address: Humboldt Universität zu Berlin, Molekulare Zellbiologie, Max-Delbrück-Haus, Robert-Rössle-Str. 10, 13122 Berlin, Germany. Phone: 49 30 94 06 33 07. Fax: 49 30 94 06 33 06. E-mail: mstraus{at}mdc.berlin.de.

Molecular and Cellular Biology, April 1999, p. 2690-2698, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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