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Molecular and Cellular Biology, August 1999, p. 5785-5799, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

NF-kappa B Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1

Denis C. Guttridge,1 Chris Albanese,2 Julie Y. Reuther,3 Richard G. Pestell,2 and Albert S. Baldwin Jr.1,4,*

Lineberger Comprehensive Cancer Center,1 Curriculum in Genetics and Molecular Biology,3 and Department of Biology,4 University of North Carolina, Chapel Hill, North Carolina 27599-7295, and Albert Einstein College of Medicine Cancer Center, Department of Developmental and Molecular Biology and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 104612

Received 22 January 1999/Returned for modification 3 March 1999/Accepted 3 May 1999

Accumulating evidence implicates the transcription factor NF-kappa B as a positive mediator of cell growth, but the molecular mechanism(s) involved in this process remains largely unknown. Here we use both a skeletal muscle differentiation model and normal diploid fibroblasts to gain insight into how NF-kappa B regulates cell growth and differentiation. Results obtained with the C2C12 myoblast cell line demonstrate that NF-kappa B functions as an inhibitor of myogenic differentiation. Myoblasts generated to lack NF-kappa B activity displayed defects in cellular proliferation and cell cycle exit upon differentiation. An analysis of cell cycle markers revealed that NF-kappa B activates cyclin D1 expression, and the results showed that this regulatory pathway is one mechanism by which NF-kappa B inhibits myogenesis. NF-kappa B regulation of cyclin D1 occurs at the transcriptional level and is mediated by direct binding of NF-kappa B to multiple sites in the cyclin D1 promoter. Using diploid fibroblasts, we demonstrate that NF-kappa B is required to induce cyclin D1 expression and pRb hyperphosphorylation and promote G1-to-S progression. Consistent with results obtained with the C2C12 differentiation model, we show that NF-kappa B also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1. These data therefore identify cyclin D1 as an important transcriptional target of NF-kappa B and reveal a mechanism to explain how NF-kappa B is involved in the early phases of the cell cycle to regulate cell growth and differentiation.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, Campus Box 7295, Mason Farm Rd., UNC School of Medicine, Chapel Hill, NC 27599-7295. Phone: (919) 966-3652. Fax: (919) 966-0444. E-mail: jhall{at}med.unc.edu.

Molecular and Cellular Biology, August 1999, p. 5785-5799, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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