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Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1.

Eischen CM, Packham G, Nip J, Fee BE, Hiebert SW, Zambetti GP, Cleveland JL
Oncogene. 2001 20 (48): 6983-93

PMID: 11704823 · DOI:10.1038/sj.onc.1204892

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.

MeSH Terms (28)

Animals Apoptosis bcl-X Protein Cell Cycle Proteins Cell Line, Transformed Cell Transformation, Neoplastic DNA DNA-Binding Proteins E2F1 Transcription Factor E2F Transcription Factors Gene Expression Regulation Genes, bcl-2 Genes, myc Genes, p53 Interleukin-3 Mice Mutation Myeloid Cells Protein Binding Protein Conformation Proto-Oncogene Proteins c-bcl-2 Proto-Oncogene Proteins c-myc Recombinant Fusion Proteins Temperature Transcription Factors Transfection Tumor Suppressor Protein p14ARF Tumor Suppressor Protein p53

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