Rel and nuclear factor (NF)-κB1, two members of the Rel/NF-κB transcription factor family, are essential for mitogen-induced B cell proliferation. Using mice with inactivated Rel or NF-κB1 genes, we show that these transcription factors differentially regulate cell cycle progression and apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell turnover in naive nfkb1−/− mice, the level of apoptosis in cultures of quiescent nfkb1−/−, but not c-rel−/−, B cells is higher. The failure of c-rel−/− or nfkb1−/− B cells to proliferate in response to particular mitogens coincides with a cell cycle block early in G1 and elevated cell death. Expression of a bcl-2 transgene prevents apoptosis in resting and activated c-rel−/− and nfkb1−/− B cells, but does not overcome the block in cell cycle progression, suggesting that the impaired proliferation is not simply a consequence of apoptosis and that Rel/NF-κB proteins regulate cell survival and cell cycle control through independent mechanisms. In contrast to certain B lymphoma cell lines in which mitogen-induced cell death can result from Rel/NF-κB–dependent downregulation of c-myc, expression of c-myc is normal in resting and stimulated c-rel−/− B cells, indicating that target gene(s) regulated by Rel that are important for preventing apoptosis may differ in normal and immortalized B cells. Collectively, these results are the first to demonstrate that in normal B cells, NF-κB1 regulates survival of cells in G0, whereas mitogenic activation induced by distinct stimuli requires different Rel/NF-κB factors to control cell cycle progression and prevent apoptosis.
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2 March 1998
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March 02 1998
B Lymphocytes Differentially Use the Rel and Nuclear Factor κB1 (NF-κB1) Transcription Factors to Regulate Cell Cycle Progression and Apoptosis in Quiescent and Mitogen-activated Cells
Raelene J. Grumont,
Raelene J. Grumont
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
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Ian J. Rourke,
Ian J. Rourke
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
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Lorraine A. O'Reilly,
Lorraine A. O'Reilly
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
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Andreas Strasser,
Andreas Strasser
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
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Kensuke Miyake,
Kensuke Miyake
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
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William Sha,
William Sha
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
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Steve Gerondakis
Steve Gerondakis
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
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Raelene J. Grumont
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
Ian J. Rourke
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
Lorraine A. O'Reilly
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
Andreas Strasser
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
Kensuke Miyake
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
William Sha
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
Steve Gerondakis
From *The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the ‡Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the §University of California, Berkeley, California 94720
The authors thank Dr. David Huang for technical advice, Dr. Frank Battye and colleagues for assistance with cell sorting, and Ms. Julie Merryfull for animal husbandry.
This work is supported by the National Health and Medical Research Council (Australia), the Anti-Cancer Council of Victoria, the Australian Cooperative Research Centre grant (No. 91007), and Commonwealth AIDS Research Grant (No. 971274).
Address correspondence to Steve Gerondakis, The Walter and Eliza Hall Institute of Medical Research, P.O. The Royal Melbourne Hospital, Victoria 3050, Australia. Phone: 61-3-93452542; Fax: 61-3-93470852; E-mail: [email protected]
1
Abbreviations used in this paper: BrdU, 5-bromo-2-deoxyuridine; mRNA, messenger RNA; PI, propidium iodide.
Received:
October 08 1997
Revision Received:
December 08 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (5): 663–674.
Article history
Received:
October 08 1997
Revision Received:
December 08 1997
Citation
Raelene J. Grumont, Ian J. Rourke, Lorraine A. O'Reilly, Andreas Strasser, Kensuke Miyake, William Sha, Steve Gerondakis; B Lymphocytes Differentially Use the Rel and Nuclear Factor κB1 (NF-κB1) Transcription Factors to Regulate Cell Cycle Progression and Apoptosis in Quiescent and Mitogen-activated Cells . J Exp Med 2 March 1998; 187 (5): 663–674. doi: https://doi.org/10.1084/jem.187.5.663
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