Differences in DNA binding properties between E2F1 and E2F4 specify repression of the Mcl-1 promoter.
E2F1 is a potent inducer of apoptosis whereas its relative, E2F4, generally does not promote cell death. Other work from our laboratory has demonstrated that E2F1 can directly bind and represss the Mcl-1 promoter - contributing to E2F1-mediated apoptosis. Here we show that while E2F1 can repress the Mcl-1 promoter, other members of the E2F family (such as E2F4) cannot. Characterization of the Mcl-1 promoter demonstrates that the -143/+10 region is critical for E2F1-mediated downregulation. We demonstrate that the ability of E2F1 to repress the Mcl-1 promoter correlates with its ability to bind within the required -143/+10 region of this promoter. In contrast, E2F4 is unable to bind to the -143/+10 region of the Mcl-1 promoter. We propose that E2F4 is unable to repress the Mcl-1 promoter primarily as a result of insufficient binding to the essential regulatory region. This is the first evidence of DNA binding specificity among E2F family members that results in differential regulation of a naturally occurring promoter.
Croxton
Rhonda
R
Program in Molecular Oncology, H Lee Moffitt Comprehensive Cancer Center and Research Institute, Tampa, Florida, FL 33612, USA.
Ma
Yihong
Y
Cress
W Douglas
WD
D016475:3T3 Cells; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050704:E2F4 Transcription Factor; D024202:Electrophoretic Mobility Shift Assay; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; C493754:E2f1 protein, mouse; C493763:E2f4 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors