Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Binding Sites; Breast Neoplasms; Cell Line, Tumor; Female; *Genome, Human; Genome-Wide Association Study; Humans; Hydrolases; Phosphorylation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos; Transcriptional Activation; ets-Domain Protein Elk-1
Biochemistry | Enzymes and Coenzymes | Genetics and Genomics | Medicinal-Pharmaceutical Chemistry | Therapeutics
Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline, and this activity has been linked to the repression of a limited number of target genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) analysis to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 breast cancer cells. Results showed that PADI4 is enriched in gene promoter regions near transcription start sites (TSSs); and, surprisingly, this pattern of binding is primarily associated with actively transcribed genes. Computational analysis found potential binding sites for Elk-1, a member of the ETS oncogene family, to be highly enriched around PADI4 binding sites; and coimmunoprecipitation analysis then confirmed that Elk-1 physically associates with PADI4. To better understand how PADI4 may facilitate gene transactivation, we then show that PADI4 interacts with Elk-1 at the c-Fos promoter and that, following Epidermal Growth Factor (EGF) stimulation, PADI4 catalytic activity facilitates Elk-1 phosphorylation, histone H4 acetylation, and c-Fos transcriptional activation. These results define a novel role for PADI4 as a transcription factor co-activator.
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Citation: PLoS Genet. 2011 Jun;7(6):e1002112. doi: 10.1371/journal.pgen.1002112. Epub 2011 Jun 2. Link to article on publisher's site
Zhang, Xuesen; Gamble, Matthew J.; Stadler, Sonja; Cherrington, Brian D.; Causey, Corey P.; Thompson, Paul R.; Roberson, Mark S.; Kraus, W Lee; and Coonrod, Scott A., "Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells." (2011). Thompson Lab Publications. 48.