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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Garcia, Benjamin A. Wakshlag, Joseph J. Stadler, Sonja C. Zee, Barry M. Coonrod, Scott A. Patsialou, Antonia Vincent, C. Theresa Mohanan, Sunish Brown, Anthony M. C. Zhang, Xuesen Allis, C. David Condeelis, John S. Cherrington, Brian D. Fedorov, Victor D. |
| Description | Author Affiliation: Stadler SC ( Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.); |
| Abstract | Peptidylarginine deiminase 4 (PAD4) is a Ca(2+)-dependent enzyme that converts arginine and methylarginine residues to citrulline, with histone proteins being among its best-described substrates to date. However, the biological function of this posttranslational modification, either in histones or in nonhistone proteins, is poorly understood. Here, we show that PAD4 recognizes, binds, and citrullinates glycogen synthase kinase-3ß (GSK3ß), both in vitro and in vivo. Among other functions, GSK3ß is a key regulator of transcription factors involved in tumor progression, and its dysregulation has been associated with progression of human cancers. We demonstrate that silencing of PAD4 in breast cancer cells leads to a striking reduction of nuclear GSK3ß protein levels, increased TGF-ß signaling, induction of epithelial-to-mesenchymal transition, and production of more invasive tumors in xenograft assays. Moreover, in breast cancer patients, reduction of PAD4 and nuclear GSK3ß is associated with increased tumor invasiveness. We propose that PAD4-mediated citrullination of GSK3ß is a unique posttranslational modification that regulates its nuclear localization and thereby plays a critical role in maintaining an epithelial phenotype. We demonstrate a dynamic and previously unappreciated interplay between histone-modifying enzymes, citrullination of nonhistone proteins, and epithelial-to-mesenchymal transition. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 29 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Citrulline Metabolism Epithelial-Mesenchymal Transition Physiology Glycogen Synthase Kinase 3 Hydrolases Signal Transduction Transforming Growth Factor Beta Calcium Ionophores Fluorescent Antibody Technique Gene Knockdown Techniques Immunoblotting Immunohistochemistry Immunoprecipitation MCF-7 Cells Mass Spectrometry Microscopy, Interference Mutagenesis, Site-Directed Real-Time Polymerase Chain Reaction Statistics, Nonparametric Research Support, American Recovery And Reinvestment Act Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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