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Keratinocyte transcriptional regulation of the human c‐Myc promoter occurs via a novel Lef/Tcf binding element distinct from neoplastic cells
Author(s) -
Kolly Carine,
Zakher Antony,
Strauss Christian,
Suter Maja M.,
Müller Eliane J.
Publication year - 2007
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.04.023
Subject(s) - transactivation , biology , transcriptional regulation , carcinogenesis , transcription factor , neoplastic transformation , keratinocyte , reporter gene , gene , oncogene , microbiology and biotechnology , transcription (linguistics) , cancer research , in vitro , genetics , gene expression , cell cycle , linguistics , philosophy
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 β‐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 β‐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.