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  • Original Paper
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Cyclin E and Bcl-xL cooperatively induce cell cycle progression in c-Rel−/− B cells

Oncogene volume 22, pages 8472–8486 (2003)Cite this article

Abstract

Aberrant overexpression of the c-rel protooncogene is associated with lymphoid malignancy, while c-rel deletion produces severe lymphoproliferative defects and immunodeficiency. To investigate the mechanism of c-rel-induced proliferation and cell cycle progression in B lymphocytes, we have compared signaling events elicited through the BCR in c-rel−/− and wild-type B cells. BCR stimulation of c-rel−/− B cells fails to induce proper cyclin expression, resulting in G1 phase arrest, but it is unclear whether these defects are in fact secondary events of decreased B-cell survival, since c-rel deletion also affects the expression of antiapoptotic genes such as bcl-xL. Here, we use the bcl-xL transgene to correct the viability of c-rel-deficient B cells, and show that the inhibition of apoptosis does not necessarily confer hyperproliferation of B cells activated through the BCR. c-rel−/− B cells still fail to enter the S phase despite improved survival by bcl-xL overexpression, suggesting that c-Rel-associated cell cycle progression is dependent on more than just enhanced cell viability. Overexpression of cyclin E protein, however, can cooperate with Bcl-xL to restore cell cycle progression to c-rel−/− B cells via induction of the cyclin–CDK/Rb–E2F pathway. Furthermore, we show that c-Rel can directly regulate transcription of the e2f3a promoter/enhancer, which is then likely to lead to transcriptional activation of the cyclin E promoter by E2F3a. Hence, these studies provide clear evidence that control of lymphocyte proliferation via c-Rel is linked to a cyclin-dependent process, and suggest that c-Rel not only activates antiapoptotic signaling but also the induction of cell cycle progression.

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Abbreviations

CDK:

cyclin-dependent kinase

IL-2:

interleukin-2

IL-4:

interleukin-4

IL-12:

interleukin-12

PI:

propidium iodide

GFP:

green fluorescent protein

CFSE:

5-(and-6)-carboxyfluoresceindiacetate succinimidyl ester

DHFR:

dihyrofolate reductase

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Acknowledgements

We thank Dr Steven Dowdy for providing the TAT-vector and various other TAT-constructs, Dr Joseph Tumang for constructing TAT-GFP, and Dr Kendall A Smith, Dr Carol Beadling, and Dr Selina Chen-Kiang for critical review of the manuscript. This work was supported by NIH Grants: CA 68155, CA 90405, and 1 T32 A1 07621 (CYH); the Cancer Research Institute Fellowship in Tumor Immunology (CYH); and the Leukemia and Lymphoma Society Scholarship.

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  1. Shuhua Cheng and Constance Yu Hsia: The first two authors contributed equally to this work

Authors and Affiliations

  1. Division of Immunology, Department of Medicine, Weill Medical College of Cornell University, New York, 10021, NY, USA

    Shuhua Cheng, Constance Yu Hsia & Hsiou-Chi Liou

  2. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, 43210, OH, USA

    Gustavo Leone

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  1. Shuhua Cheng
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Correspondence to Hsiou-Chi Liou.

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Cheng, S., Hsia, C., Leone, G. et al. Cyclin E and Bcl-xL cooperatively induce cell cycle progression in c-Rel−/− B cells. Oncogene 22, 8472–8486 (2003). https://doi.org/10.1038/sj.onc.1206917

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