title: BRD4 Phosphorylation Regulates HPV E2-Mediated Viral Transcription, Origin Replication, and Cellular MMP-9 Expression.
abstract: Post-translational modification can modulate protein conformation and alter binding partner recruitment within gene regulatory regions. Here, we report that bromodomain-containing protein 4 (BRD4), a transcription co-factor and chromatin regulator, uses a phosphorylation-induced switch mechanism to recruit E2 protein encoded by cancer-associated human papillomavirus (HPV) to viral early gene and cellular matrix metalloproteinase-9 (MMP-9) promoters. Enhanced MMP-9 expression, induced upon keratinocyte differentiation, occurs via BRD4-dependent recruitment of active AP-1 and NF-κB to their target sequences. This is triggered by replacement of AP-1 family members JunB and JunD by c-Jun and by re-localization of NF-κB from the cytoplasm to the nucleus. In addition, BRD4 phosphorylation is critical for E2- and origin-dependent HPV DNA replication. A class of phospho-BRD4-targeting compounds, distinct from the BET bromodomain inhibitors, effectively blocks BRD4 phosphorylation-specific functions in transcription and factor recruitment.
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Dawn Sijin
authors.initials: DS
authors.lastname: Nin
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: A-Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Simanski
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kodadek
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: cheng-ming.chiang@utsouthwestern.edu.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
mesh_terms: D018797:Cell Cycle Proteins; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D027383:Papillomaviridae / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C579270:MMP9 protein, human