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Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells.

PLoS genetics | Jun 9, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21655091

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.

Pubmed ID: 21655091 RIS Download

Mesh terms: 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

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK069710
  • Agency: NIDDK NIH HHS, Id: DK58110
  • Agency: NIDDK NIH HHS, Id: R01 DK058110

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