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Molecular and Cellular Biology, March 2001, p. 1930-1941, Vol. 21, No. 6
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.6.1930-1941.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Ikappa B Kinase-Dependent Chronic Activation of NF-kappa B Is Necessary for p21WAF1/Cip1 Inhibition of Differentiation-Induced Apoptosis of Monocytes

Kevin N. Pennington,1 Julie A. Taylor,1 Gary D. Bren,1 and Carlos V. Paya1,2,*

Department of Immunology1 and Division of Infectious Diseases,2 Mayo Clinic, Rochester, Minnesota 55905

Received 8 September 2000/Accepted 11 December 2000

The molecular mechanisms regulating monocyte differentiation to macrophages remain unknown. Although the transcription factor NF-kappa B participates in multiple cell functions, its role in cell differentiation is ill defined. Since differentiated macrophages, in contrast to cycling monocytes, contain significant levels of NF-kappa B in the nuclei, we questioned whether this transcription factor is involved in macrophage differentiation. Phorbol 12-myristate 13-acetate (PMA)-induced differentiation of the promonocytic cell line U937 leads to persistent NF-kappa B nuclear translocation. We demonstrate here that an increased and persistent IKK activity correlates with monocyte differentiation leading to persistent NF-kappa B activation secondary to increased Ikappa Balpha degradation via the Ikappa B signal response domain (SRD). Promonocytic cells stably overexpressing an Ikappa Balpha transgene containing SRD mutations fail to activate NF-kappa B and subsequently fail to survive the PMA-induced macrophage differentiation program. The differentiation-induced apoptosis was found to be dependent on tumor necrosis factor alpha. The protective effect of NF-kappa B is mediated through p21WAF1/Cip1, since this protein was found to be regulated in an NF-kappa B-dependent manner and to confer survival features during macrophage differentiation. Therefore, NF-kappa B plays a key role in cell differentiation by conferring cell survival that in the case of macrophages is mediated through p21WAF1/Cip1.

* Corresponding author. Mailing address: Mayo Clinic, 200 First Street, SW, Guggenheim 501, Rochester, MN 55905. Phone: (507) 284-3747. Fax: (507) 284-3757. E-mail: paya{at}mayo.edu.

Molecular and Cellular Biology, March 2001, p. 1930-1941, Vol. 21, No. 6
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.6.1930-1941.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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