Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1996 Dec 16;15(24):6979–6990.

The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry.

L A O'Reilly 1, D C Huang 1, A Strasser 1
PMCID: PMC452524  PMID: 9003774

Abstract

The effect of the cell death inhibitor Bcl-2 and its homologues on cell cycle regulation was explored in lymphocytes and cell lines. Expression of a bcl-2 transgene reduced proliferation of thymocytes and delayed cell cycle entry of mitogen-stimulated B and T lymphocytes. Overexpression of Bcl-2, Bcl-xL or adenovirus E1B19kD substantially delayed serum stimulation-induced S phase entry of quiescent NIH 3T3 fibroblasts. Bcl-2-mediated cell survival and growth inhibition are both antagonized by Bax. Bcl-2, Bcl-xL and E1B19kD, but not Bcl-2 mutants that are defective in blocking apoptosis, suppress growth of colon carcinoma cells. This evidence that regulation of cell survival is coupled to control of cell growth has implications for normal cell turnover and tumorigenesis.

Full text

PDF

Images in this article

6981Image
on p.6981
6984Image
on p.6984

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Askew D. S., Ashmun R. A., Simmons B. C., Cleveland J. L. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene. 1991 Oct;6(10):1915–1922. [PubMed] [Google Scholar]
  2. Blanar M. A., Rutter W. J. Interaction cloning: identification of a helix-loop-helix zipper protein that interacts with c-Fos. Science. 1992 May 15;256(5059):1014–1018. doi: 10.1126/science.1589769. [DOI] [PubMed] [Google Scholar]
  3. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  4. Borner C., Martinou I., Mattmann C., Irmler M., Schaerer E., Martinou J. C., Tschopp J. The protein bcl-2 alpha does not require membrane attachment, but two conserved domains to suppress apoptosis. J Cell Biol. 1994 Aug;126(4):1059–1068. doi: 10.1083/jcb.126.4.1059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brancolini C., Benedetti M., Schneider C. Microfilament reorganization during apoptosis: the role of Gas2, a possible substrate for ICE-like proteases. EMBO J. 1995 Nov 1;14(21):5179–5190. doi: 10.1002/j.1460-2075.1995.tb00202.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cheng E. H., Levine B., Boise L. H., Thompson C. B., Hardwick J. M. Bax-independent inhibition of apoptosis by Bcl-XL. Nature. 1996 Feb 8;379(6565):554–556. doi: 10.1038/379554a0. [DOI] [PubMed] [Google Scholar]
  7. Chiou S. K., Rao L., White E. Bcl-2 blocks p53-dependent apoptosis. Mol Cell Biol. 1994 Apr;14(4):2556–2563. doi: 10.1128/mcb.14.4.2556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cory S. Regulation of lymphocyte survival by the bcl-2 gene family. Annu Rev Immunol. 1995;13:513–543. doi: 10.1146/annurev.iy.13.040195.002501. [DOI] [PubMed] [Google Scholar]
  9. Cory S., Strasser A., Jacks T., Corcoran L. M., Metz T., Harris A. W., Adams J. M. Enhanced cell survival and tumorigenesis. Cold Spring Harb Symp Quant Biol. 1994;59:365–375. doi: 10.1101/sqb.1994.059.01.041. [DOI] [PubMed] [Google Scholar]
  10. Debbas M., White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev. 1993 Apr;7(4):546–554. doi: 10.1101/gad.7.4.546. [DOI] [PubMed] [Google Scholar]
  11. Egerton M., Scollay R., Shortman K. Kinetics of mature T-cell development in the thymus. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2579–2582. doi: 10.1073/pnas.87.7.2579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ellis H. M., Horvitz H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell. 1986 Mar 28;44(6):817–829. doi: 10.1016/0092-8674(86)90004-8. [DOI] [PubMed] [Google Scholar]
  13. Ellis R. E., Yuan J. Y., Horvitz H. R. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. doi: 10.1146/annurev.cb.07.110191.003311. [DOI] [PubMed] [Google Scholar]
  14. Evan G. I., Wyllie A. H., Gilbert C. S., Littlewood T. D., Land H., Brooks M., Waters C. M., Penn L. Z., Hancock D. C. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. doi: 10.1016/0092-8674(92)90123-t. [DOI] [PubMed] [Google Scholar]
  15. Fanidi A., Harrington E. A., Evan G. I. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature. 1992 Oct 8;359(6395):554–556. doi: 10.1038/359554a0. [DOI] [PubMed] [Google Scholar]
  16. Fernandez-Sarabia M. J., Bischoff J. R. Bcl-2 associates with the ras-related protein R-ras p23. Nature. 1993 Nov 18;366(6452):274–275. doi: 10.1038/366274a0. [DOI] [PubMed] [Google Scholar]
  17. Fulcher D. A., Basten A. Reduced life span of anergic self-reactive B cells in a double-transgenic model. J Exp Med. 1994 Jan 1;179(1):125–134. doi: 10.1084/jem.179.1.125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harrington E. A., Bennett M. R., Fanidi A., Evan G. I. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 1994 Jul 15;13(14):3286–3295. doi: 10.1002/j.1460-2075.1994.tb06630.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hengartner M. O., Ellis R. E., Horvitz H. R. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature. 1992 Apr 9;356(6369):494–499. doi: 10.1038/356494a0. [DOI] [PubMed] [Google Scholar]
  20. Hengartner M. O., Horvitz H. R. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell. 1994 Feb 25;76(4):665–676. doi: 10.1016/0092-8674(94)90506-1. [DOI] [PubMed] [Google Scholar]
  21. Hengartner M. O., Horvitz H. R. Programmed cell death in Caenorhabditis elegans. Curr Opin Genet Dev. 1994 Aug;4(4):581–586. doi: 10.1016/0959-437x(94)90076-f. [DOI] [PubMed] [Google Scholar]
  22. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  23. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  24. Korsmeyer S. J. Regulators of cell death. Trends Genet. 1995 Mar;11(3):101–105. doi: 10.1016/S0168-9525(00)89010-1. [DOI] [PubMed] [Google Scholar]
  25. Kumar S. ICE-like proteases in apoptosis. Trends Biochem Sci. 1995 May;20(5):198–202. doi: 10.1016/s0968-0004(00)89007-6. [DOI] [PubMed] [Google Scholar]
  26. Levy R., Levy S., Cleary M. L., Carroll W., Kon S., Bird J., Sklar J. Somatic mutation in human B-cell tumors. Immunol Rev. 1987 Apr;96:43–58. doi: 10.1111/j.1600-065x.1987.tb00508.x. [DOI] [PubMed] [Google Scholar]
  27. Linette G. P., Grusby M. J., Hedrick S. M., Hansen T. H., Glimcher L. H., Korsmeyer S. J. Bcl-2 is upregulated at the CD4+ CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity. 1994 Jun;1(3):197–205. doi: 10.1016/1074-7613(94)90098-1. [DOI] [PubMed] [Google Scholar]
  28. Linette G. P., Hess J. L., Sentman C. L., Korsmeyer S. J. Peripheral T-cell lymphoma in lckpr-bcl-2 transgenic mice. Blood. 1995 Aug 15;86(4):1255–1260. [PubMed] [Google Scholar]
  29. Lithgow T., van Driel R., Bertram J. F., Strasser A. The protein product of the oncogene bcl-2 is a component of the nuclear envelope, the endoplasmic reticulum, and the outer mitochondrial membrane. Cell Growth Differ. 1994 Apr;5(4):411–417. [PubMed] [Google Scholar]
  30. Martin S. J., McGahon A. J., Nishioka W. K., LaFace D., Guo X., Th'ng J., Bradbury E. M., Green D. R. p34cdc2 and apoptosis. Science. 1995 Jul 7;269(5220):106–107. doi: 10.1126/science.7604270. [DOI] [PubMed] [Google Scholar]
  31. Marvel J., Perkins G. R., Lopez Rivas A., Collins M. K. Growth factor starvation of bcl-2 overexpressing murine bone marrow cells induced refractoriness to IL-3 stimulation of proliferation. Oncogene. 1994 Apr;9(4):1117–1122. [PubMed] [Google Scholar]
  32. Mazel S., Burtrum D., Petrie H. T. Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death. J Exp Med. 1996 May 1;183(5):2219–2226. doi: 10.1084/jem.183.5.2219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. McDonnell T. J., Korsmeyer S. J. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature. 1991 Jan 17;349(6306):254–256. doi: 10.1038/349254a0. [DOI] [PubMed] [Google Scholar]
  34. Miyashita T., Reed J. C. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res. 1992 Oct 1;52(19):5407–5411. [PubMed] [Google Scholar]
  35. Mizushima S., Nagata S. pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 1990 Sep 11;18(17):5322–5322. doi: 10.1093/nar/18.17.5322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Motoyama N., Wang F., Roth K. A., Sawa H., Nakayama K., Nakayama K., Negishi I., Senju S., Zhang Q., Fujii S. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science. 1995 Mar 10;267(5203):1506–1510. doi: 10.1126/science.7878471. [DOI] [PubMed] [Google Scholar]
  37. Nossal G. J. Negative selection of lymphocytes. Cell. 1994 Jan 28;76(2):229–239. doi: 10.1016/0092-8674(94)90331-x. [DOI] [PubMed] [Google Scholar]
  38. Nuñez G., London L., Hockenbery D., Alexander M., McKearn J. P., Korsmeyer S. J. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990 May 1;144(9):3602–3610. [PubMed] [Google Scholar]
  39. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  40. Pezzella F., Tse A. G., Cordell J. L., Pulford K. A., Gatter K. C., Mason D. Y. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990 Aug;137(2):225–232. [PMC free article] [PubMed] [Google Scholar]
  41. Pietenpol J. A., Papadopoulos N., Markowitz S., Willson J. K., Kinzler K. W., Vogelstein B. Paradoxical inhibition of solid tumor cell growth by bcl2. Cancer Res. 1994 Jul 15;54(14):3714–3717. [PubMed] [Google Scholar]
  42. Rao L., Debbas M., Sabbatini P., Hockenbery D., Korsmeyer S., White E. The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7742–7746. doi: 10.1073/pnas.89.16.7742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rolink A., Melchers F. Molecular and cellular origins of B lymphocyte diversity. Cell. 1991 Sep 20;66(6):1081–1094. doi: 10.1016/0092-8674(91)90032-t. [DOI] [PubMed] [Google Scholar]
  44. Sentman C. L., Shutter J. R., Hockenbery D., Kanagawa O., Korsmeyer S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. doi: 10.1016/0092-8674(91)90361-2. [DOI] [PubMed] [Google Scholar]
  45. Shi L., Nishioka W. K., Th'ng J., Bradbury E. M., Litchfield D. W., Greenberg A. H. Premature p34cdc2 activation required for apoptosis. Science. 1994 Feb 25;263(5150):1143–1145. doi: 10.1126/science.8108732. [DOI] [PubMed] [Google Scholar]
  46. Siegel R. M., Katsumata M., Miyashita T., Louie D. C., Greene M. I., Reed J. C. Inhibition of thymocyte apoptosis and negative antigenic selection in bcl-2 transgenic mice. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7003–7007. doi: 10.1073/pnas.89.15.7003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sprent J. T and B memory cells. Cell. 1994 Jan 28;76(2):315–322. doi: 10.1016/0092-8674(94)90338-7. [DOI] [PubMed] [Google Scholar]
  48. Strasser A., Harris A. W., Bath M. L., Cory S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature. 1990 Nov 22;348(6299):331–333. doi: 10.1038/348331a0. [DOI] [PubMed] [Google Scholar]
  49. Strasser A., Harris A. W., Cory S. E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. Oncogene. 1993 Jan;8(1):1–9. [PubMed] [Google Scholar]
  50. Strasser A., Harris A. W., Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. doi: 10.1016/0092-8674(91)90362-3. [DOI] [PubMed] [Google Scholar]
  51. Strasser A., Harris A. W., Huang D. C., Krammer P. H., Cory S. Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J. 1995 Dec 15;14(24):6136–6147. doi: 10.1002/j.1460-2075.1995.tb00304.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Strasser A., Harris A. W., Jacks T., Cory S. DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell. 1994 Oct 21;79(2):329–339. doi: 10.1016/0092-8674(94)90201-1. [DOI] [PubMed] [Google Scholar]
  53. Strasser A., Harris A. W., von Boehmer H., Cory S. Positive and negative selection of T cells in T-cell receptor transgenic mice expressing a bcl-2 transgene. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1376–1380. doi: 10.1073/pnas.91.4.1376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Strasser A., Whittingham S., Vaux D. L., Bath M. L., Adams J. M., Cory S., Harris A. W. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8661–8665. doi: 10.1073/pnas.88.19.8661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Taylor I. W. A rapid single step staining technique for DNA analysis by flow microfluorimetry. J Histochem Cytochem. 1980 Sep;28(9):1021–1024. doi: 10.1177/28.9.6157714. [DOI] [PubMed] [Google Scholar]
  56. Thompson C. B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456–1462. doi: 10.1126/science.7878464. [DOI] [PubMed] [Google Scholar]
  57. Vairo G., Innes K. M., Adams J. M. Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. Oncogene. 1996 Oct 3;13(7):1511–1519. [PubMed] [Google Scholar]
  58. Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
  59. Vaux D. L., Haecker G., Strasser A. An evolutionary perspective on apoptosis. Cell. 1994 Mar 11;76(5):777–779. doi: 10.1016/0092-8674(94)90350-6. [DOI] [PubMed] [Google Scholar]
  60. Vaux D. L., Weissman I. L., Kim S. K. Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science. 1992 Dec 18;258(5090):1955–1957. doi: 10.1126/science.1470921. [DOI] [PubMed] [Google Scholar]
  61. Veis D. J., Sorenson C. M., Shutter J. R., Korsmeyer S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993 Oct 22;75(2):229–240. doi: 10.1016/0092-8674(93)80065-m. [DOI] [PubMed] [Google Scholar]
  62. White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
  63. White E., Sabbatini P., Debbas M., Wold W. S., Kusher D. I., Gooding L. R. The 19-kilodalton adenovirus E1B transforming protein inhibits programmed cell death and prevents cytolysis by tumor necrosis factor alpha. Mol Cell Biol. 1992 Jun;12(6):2570–2580. doi: 10.1128/mcb.12.6.2570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  65. Yin X. M., Oltvai Z. N., Korsmeyer S. J. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature. 1994 May 26;369(6478):321–323. doi: 10.1038/369321a0. [DOI] [PubMed] [Google Scholar]
  66. Yonish-Rouach E., Resnitzky D., Lotem J., Sachs L., Kimchi A., Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature. 1991 Jul 25;352(6333):345–347. doi: 10.1038/352345a0. [DOI] [PubMed] [Google Scholar]
  67. Yuan J., Shaham S., Ledoux S., Ellis H. M., Horvitz H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993 Nov 19;75(4):641–652. doi: 10.1016/0092-8674(93)90485-9. [DOI] [PubMed] [Google Scholar]
  68. von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol. 1990;8:531–556. doi: 10.1146/annurev.iy.08.040190.002531. [DOI] [PubMed] [Google Scholar]
  69. von Boehmer H. Positive selection of lymphocytes. Cell. 1994 Jan 28;76(2):219–228. doi: 10.1016/0092-8674(94)90330-1. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES