Opposite transcriptional activity between the wild type c-myc gene coding for c-Myc1 and c-Myc2 proteins and c-Myc1 and c-Myc2 separately.
E-cadherin expression was previously shown to be activated by RB and c-myc specifically in epithelial cells, through interaction with the AP-2 transcription factor. Here we show that only a wild type c-myc gene, coding for the two c-Myc proteins c-Myc2 and c-Myc1, was able to transactivate the E-cadherin promoter, in contrast to c-Myc2 or c-Myc1 alone which strongly repressed E-cadherin in both epithelial cells and fibroblasts. In addition, overexpression of c-myc2 or c-myc1 inhibited c-myc and RB-mediated activation in a dose-dependent manner, suggesting that the ratio of the two c-Myc proteins is essential for transactivation. We also showed by using several mutants of the E-cadherin promoter, that the AP-2 binding sites were the main target of c-myc2- and c-myc1-mediated repression. AP-2-mediated inhibition was cell-type specific, as was the activation. Nevertheless, when high amounts of c-myc2 and c-myc1 were used, a second c-myc-mediated repression was observed, possibly mediated by the Inr sequence of the E-cadherin promoter. However, this repression was independent of cell type. Our results suggest a new way to regulate c-myc transcriptional activity by interfering with the ratio of the two c-myc proteins, which has already been found to be disrupted in vivo in several tumor types.
Batsché
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CJF INSERM 94-02, Université René Descartes, 45 rue des Saints-Pères, 75270 Paris cedex 06, France.
Crémisi
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D016475:3T3 Cells; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D017930:Genes, Reporter; D016161:Genes, Retinoblastoma; D016259:Genes, myc; D006801:Humans; D007668:Kidney; D051379:Mice; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D016160:Retinoblastoma Protein / Q000502:physiology; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D029867:Xenopus Proteins
D015820:Cadherins; D004268:DNA-Binding Proteins; C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D029867:Xenopus Proteins; C069482:c-myc II protein, Xenopus