Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 15, Pages 6864-6869Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1002746107
Keywords
cell fate determination; Forkhead protein; transcription factor; tumor suppressor; dachshund homolog 1
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Funding
- Susan Komen Breast Cancer Foundation [BCTR0504227]
- National Institutes of Health Cancer Center Core [R01CA70896, R01CA75503, R01CA86072, R01CA080250, R01CA098779, R01CA120876, R01AR055660, 232240, P30CA56036]
- Margaret Q. Landenberger Research Foundation
- Pennsylvania Department of Health
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The Drosophila Dachshund (Dac) gene, cloned as a dominant inhibitor of the hyperactive growth factor mutant ellipse, encodes a key component of the retinal determination gene network that governs cell fate. Herein, cyclic amplification and selection of targets identified a DACH1 DNA-binding sequence that resembles the FOX (Forkhead box-containing protein) binding site. Genome-wide in silico promoter analysis of DACH1 binding sites identified gene clusters populating cellular pathways associated with the cell cycle and growth factor signaling. ChIP coupled with high-throughput sequencing mapped DACH1 binding sites to corresponding gene clusters predicted in silico and identified as weight matrix resembling the cyclic amplification and selection of targets-defined sequence. DACH1 antagonized FOXM1 target gene expression, promoter occupancy in the context of local chromatin, and contact-independent growth. Attenuation of FOX function by the cell fate determination pathway has broad implications given the diverse role of FOX proteins in cellular biology and tumorigenesis.
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