Oncoprotein E7 from Beta Human Papillomavirus 38 Induces Formation of an Inhibitory Complex for a Subset of p53-Regulated Promoters
| Autor: | Hector Hernandez-Vargas, Francesca Guarino, Rosita Accardi, Marie-Pierre Cros, Bakary S. Sylla, Massimo Tommasino, Djamel Saidj |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Keratinocytes
Papillomavirus E7 Proteins Fluorescent Antibody Technique Mice p53 function 0302 clinical medicine Gene expression DNA (Cytosine-5-)-Methyltransferases NF-kB RNA Small Interfering Luciferases Promoter Regions Genetic Papillomaviridae Cells Cultured protein EZH2 IKK-Beta p73 transforming properties 0303 health sciences Reverse Transcriptase Polymerase Chain Reaction EZH2 NF-kappa B Polycomb Repressive Complex 2 Nuclear Proteins Virus-Cell Interactions I-kappa B Kinase 3. Good health DNA-Binding Proteins Histone 030220 oncology & carcinogenesis DNA methylation DNA (Cytosine-5-)-Methyltransferase 1 Chromatin Immunoprecipitation Blotting Western Immunology Biology Real-Time Polymerase Chain Reaction Microbiology DNA methyltransferase Colony-Forming Units Assay 03 medical and health sciences Virology Animals Humans Immunoprecipitation Enhancer of Zeste Homolog 2 Protein RNA Messenger Epigenetics 030304 developmental biology Tumor Suppressor Proteins Papillomavirus Infections Tumor Protein p73 Promoter Fibroblasts Molecular biology Insect Science biology.protein Tumor Suppressor Protein p53 Chromatin immunoprecipitation |
| Zdroj: | Journal of Virology; Vol 87 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.01047-13 |
| Popis: | Our previous studies on cutaneous beta human papillomavirus 38 (HPV38) E6 and E7 oncoproteins highlighted a novel activity of IκB kinase beta (IKKβ) in the nucleus of human keratinocytes, where it phosphorylates and stabilizes ΔNp73α, an antagonist of p53/p73 functions. Here, we further characterize the role of the IKKβ nuclear form. We show that IKKβ nuclear translocation and ΔNp73α accumulation are mediated mainly by HPV38 E7 oncoprotein. Chromatin immunoprecipitation (ChIP)/Re-ChIP experiments showed that ΔNp73α and IKKβ are part, together with two epigenetic enzymes DNA methyltransferase 1 (DNMT1) and the enhancer of zeste homolog 2 (EZH2), of a transcriptional regulatory complex that inhibits the expression of some p53-regulated genes, such as PIG3 . Recruitment to the PIG3 promoter of EZH2 and DNMT1 resulted in trimethylation of histone 3 on lysine 27 and in DNA methylation, respectively, both events associated with gene expression silencing. Decreases in the intracellular levels of HPV38 E7 or ΔNp73α strongly affected the recruitment of the inhibitory transcriptional complex to the PIG3 promoter, with consequent restoration of p53-regulated gene expression. Finally, the ΔNp73α/IKKβ/DNMT1/EZH2 complex appears to bind a subset of p53-regulated promoters. In fact, the complex is efficiently recruited to several promoters of genes encoding proteins involved in DNA repair and apoptosis, whereas it does not influence the expression of the prosurvival factor Survivin. In summary, our data show that HPV38 via E7 protein promotes the formation of a multiprotein complex that negatively regulates the expression of several p53-regulated genes. |
| Databáze: | OpenAIRE |
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