Keratinocyte transcriptional regulation of the human c-Myc promoter occurs via a novel Lef/Tcf binding element distinct from neoplastic cells.
The proto-oncogene c-Myc is involved in early neoplastic transformations. Two consensus Lef/Tcf binding elements (TBE) were found to be prerequisite for transcriptional transactivation by the armadillo proteins beta-catenin and plakoglobin (PG) together with Tcf4 in human neoplastic cells. In epidermal keratinocytes, c-Myc was reported to be repressed by Lef-1 and PG. Using reporter gene assays, here we demonstrate that deletion of the two consensus TBE fails to abrogate transcriptional regulation by Lef-1/PG in wildtype and beta-catenin-/- keratinocytes, while it reduces transcription in pre-neoplastic PG-/- keratinocytes. We identified a TBE sequence variant downstream of the major transcriptional initiation site that binds Lef-1 in vitro and in vivo, and its mutation compromised transcriptional regulation by Lef-1/PG. Collectively, this study demonstrates that the two consensus TBE's reported in neoplastic cells are dispensable for c-Myc regulation in normal keratinocytes, which instead use a novel TBE sequence variant. This unprecedented finding may have important implications for armadillo target genes involved in carcinogenesis.
Kolly
Carine
C
Molecular Dermatology, Institute of Animal Pathology, Vetsuisse Faculty, 3012 Bern, Switzerland.
Zakher
Antony
A
Strauss
Christian
C
Suter
Maja M
MM
Müller
Eliane J
EJ
D000818:Animals; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D017384:Sequence Deletion; D014158:Transcription, Genetic; D051185:gamma Catenin / Q000172:deficiency
D051821:Lymphoid Enhancer-Binding Factor 1; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D051185:gamma Catenin