title: Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1.
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.
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Eischen
authors.forename: G
authors.initials: G
authors.lastname: Packham
authors.forename: J
authors.initials: J
authors.lastname: Nip
authors.forename: B E
authors.initials: BE
authors.lastname: Fee
authors.forename: S W
authors.initials: SW
authors.lastname: Hiebert
authors.forename: G P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: J L
authors.initials: JL
authors.lastname: Cleveland
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D019254:Genes, bcl-2; D016259:Genes, myc; D016158:Genes, p53; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D004247:DNA