Cloning of an ETS-Related Transcription Factor Involved in a Novel Epigenetic Mechanism of Mammary Carcinogenesis
Abstract
Previous studies demonstrated that activating Hrasl mutations found in NMU-induced rat mammary tumors arise as background mutations within the developing gland, and that carcinogenic doses of NMU induce the tumorigenic outgrowth of these mutants via epigenetic mechanisms. Analysis of DNA sequence comprising the Hrasl promoter revealed a mammary-specific DNA conformation (CS) which was disrupted by NMU exposure. When we compared the binding of proteins among cell types to an ets-like response element present within the CS region, we detected the formation of mammary specific DNA complexes. Using sequence specific DNA affinity chromatography, we purified microgram% of two proteins with estimated molecular weights of 42-43 and 37-38 kDa that are present in mammary cells and bind specifically to this promoter element. Amino acid sequencing by tandom mass spectrometry indicated that both proteins include peptides corresponding to highly conserved sequences present in a family of transcription factors. These finding suggest that carcinogen disruption of the CS could permit binding of transcription factors such as CBF-A and lead to deregulation Hrasl expression. Characterization of these binding proteins and their role in regulation of tissue specific gene expression should provide insight into epigenetic mammary carcinogenesis in rats and humans.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 1999
- Accession Number
- ADA381305
Entities
People
- Helmut Zarbl