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  • Original Paper
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Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1

Oncogene volume 20, pages 6983–6993 (2001)Cite this article

Abstract

Malignant transformation occurs in cells that overexpress c-Myc or that inappropriately activate E2F-1. Transformation occurs after the selection of cells that have acquired resistance to apoptosis that is triggered by these oncogenes, and a key mediator of this cell death process is the p53 tumor suppressor. In IL-3-dependent immortal 32D.3 myeloid cells the ARF/p53 apoptotic pathway is inactivated, as these cells fail to express ARF. Nonetheless, both c-Myc and E2F-1 overexpression accelerated apoptosis when these cells were deprived of IL-3. Here we report that c-Myc or E2F-1 overexpression suppresses Bcl-2 protein and RNA levels, and that restoration of Bcl-2 protein effectively blocks the accelerated apoptosis that occurs when c-Myc- or E2F-1-overexpressing cells are deprived of IL-3. Blocking p53 activity with mutant p53 did not abrogate E2F-1-induced suppression of Bcl-2. Analysis of immortal myeloid cells engineered to overexpress c-Myc and E2F-1 DNA binding mutants revealed that DNA binding activity of these oncoproteins is required to suppress Bcl-2 expression. These results suggest that the targeting of Bcl-2 family members is an important mechanism of oncogene-induced apoptosis, and that this occurs independent of the ARF/p53 pathway.

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Acknowledgements

We appreciate the outstanding technical support of Hui Yang, Chunying Yang, X He, and Elsie White and thank Drs Robert Hawley and Derek Persons for kindly providing retroviral expression vectors. This work was supported in part by National Institutes of Health grants CA76379 and DK44158 (JL Cleveland), CA63230 (GP Zambetti), CA64140 and CA77274 (SW Hiebert), Leukemia and Lymphoma Society Special Fellowship (formerly the Leukemia Society of America) 3827-99 (J Nip), Cancer Center Core grant CA-21765, NIH Postdoctoral Grant CA81695 (CM Eischen) and by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital.

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Author notes

  1. Christine M Eischen and Graham Packham: CM Eischen and G Packham contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Christine M Eischen, Brian E Fee, Gerard P Zambetti & John L Cleveland

  2. CRC Wessex Medical Oncology Unit, Southampton General Hospital, Southampton, SO16 6YD, UK

    Graham Packham

  3. Unilever Research US, Edgewater, NJ 07020, USA

    John Nip

  4. Department of Biochemistry, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Scott W Hiebert

  5. Department of Biochemistry, University of Tennessee, Memphis, 38163, Tennessee, USA

    Gerard P Zambetti & John L Cleveland

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  1. Christine M Eischen
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Correspondence to John L Cleveland.

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Eischen, C., Packham, G., Nip, J. et al. Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1. Oncogene 20, 6983–6993 (2001). https://doi.org/10.1038/sj.onc.1204892

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