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  • Original Paper
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Bcl-2 inhibition of T-cell proliferation is related to prolonged T-cell survival

Oncogene volume 23, pages 3770–3780 (2004)Cite this article

Abstract

Bcl-2 promotes oncogenesis by inhibiting cell death. Bcl-2 also inhibits proliferation and suppresses tumorigenesis in some settings. To clarify the role of the antiproliferative function of Bcl-2, mice expressing a mutant form of Bcl-2 reported to lack antiproliferative activity were generated (tyrosine 28 to alanine, Bcl-2-Y28A). As expected, both wild type (WT) and Bcl-2-Y28A inhibited apoptosis similarly. In contrast to previous results in cell lines, Bcl-2-Y28A inhibited T-cell proliferation identical to WT-Bcl-2. Significantly, both Bcl-2-Y28A and WT-Bcl-2 inhibited proliferation of T cells isolated from older animals, but not proliferation of T cells from immature mice. Instead, inhibition of cell activation correlated with T-cell size, p27 levels, and RNA content, all indicators of quiescent G0 arrest. Consistent with this model, Bcl-2 inhibition of T-cell proliferation was reversed by expression of Bax, again correlating cell proliferation with cell size. These experiments do not support genetically separate effects of Bcl-2 on apoptosis and proliferation. Instead, the data support a model in which Bcl-2 and Bax regulate T-cell proliferation by changes in T-cell size and by increasing the markers of quiescent G0 arrest. These changes likely result from prolonged T-cell survival.

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Acknowledgements

Transgenic mice were generated and maintained at the University of Iowa Transgenic Animal Facility that is supported in part by the Roy J and Lucille P Carver College of Medicine and the Diabetes and Endocrinology Research Center. We acknowledge Jason Luke and Joe Lenz for expert technical assistance and Norma Sinclair, Lucy Robbins, Kelly Andringa and Patricia Lovell in the Transgenic Facility for generation of mice described herein. We also thank Curt D Sigmund who is the director of the Transgenic Animal Facility. We thank Susan Shaffer and Jennifer Greer for expert assistance with manuscript preparation. YMJ is supported in part by the NIH training grant T32GM08554. This work was supported by the American Cancer Society (Grant IN-122T to C.M.K.) and NIH grants 1RO1CA78443 (EY) and 1RO1CA88967 (CMK). CMK is a Charles E Culpeper Medical Scholar, and the work was supported by the Rockefeller Brothers Fund.

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Authors and Affiliations

  1. Department of Pathology, The University of Iowa Roy J and Lucille P Carver College of Medicine, 3160 ML, Iowa City, 52242, IA, USA

    Ningli Cheng, Lisa Didion, Chris Van Hofwegen & C Michael Knudson

  2. Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, 37232, TN, USA

    Yelena M Janumyan & Elizabeth Yang

  3. Department of Pediatrics, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, 37232, TN, USA

    Elizabeth Yang

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  1. Ningli Cheng
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Correspondence to C Michael Knudson.

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Cheng, N., Janumyan, Y., Didion, L. et al. Bcl-2 inhibition of T-cell proliferation is related to prolonged T-cell survival. Oncogene 23, 3770–3780 (2004). https://doi.org/10.1038/sj.onc.1207478

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