Identification of an epithelial-specific enhancer regulating ESX expression.
The Ets transcription factor, ESX, exhibits a unique pattern of epithelial-restricted expression and transactivates genes involved in epithelial differentiation and cancer. The aim of this study was to determine the underlying genetic basis for epithelial-specific expression of ESX. We have identified a 30bp ESX enhancer sequence (EES) approximately 3 kb upstream of the proximal promoter. This region displays enhancer activity in an epithelial-specific manner and deletion of this region abrogates ESX gene transcription. An EES binding protein complex (EBC) was identified through electrophoretic mobility shift assays whose degree of EES binding correlated well with endogenous ESX levels in epithelial cells and was regulated by epithelial differentiation. Understanding the regulation of this element will lend insight into mechanisms of epithelial differentiation and the etiology of breast cancer and may provide novel targets for cancer therapeutic intervention.
Neve
Richard M
RM
Cancer Research Institute, University of California San Francisco, Box 0808, San Francisco, CA 94143-0808, USA. rmneve@lbl.gov
Parmar
Hema
H
Amend
Cliff
C
Chen
Chira
C
Rizzino
Angie
A
Benz
Christopher C
CC
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic; D004847:Epithelial Cells / Q000378:metabolism; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D015533:Transcriptional Activation
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D050783:Proto-Oncogene Proteins c-ets; D008156:Luciferases