BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase
| Autor: | Irmgard Irminger-Finger, Anis Feki, Laetitia Cartier, Philip Berardi, Charles Edward Jefford, Jian-Yu Wu, Karl-Heinz Krause |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
DNA damage Ubiquitin-Protein Ligases Green Fluorescent Proteins Molecular Sequence Data Apoptosis DNA-Activated Protein Kinase Protein Serine-Threonine Kinases ddc:616.07 Biology Catalysis Cell Line Phosphorylation cascade DNA-Binding Proteins/ physiology 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Genetics Humans Amino Acid Sequence Phosphorylation Molecular Biology Green Fluorescent Proteins/metabolism 030304 developmental biology Inhibitor of apoptosis domain Protein-Serine-Threonine Kinases/ physiology 0303 health sciences Tumor Suppressor Protein p53/ metabolism Kinase Tumor Suppressor Proteins Nuclear Proteins Ubiquitin-Protein Ligases/genetics/ physiology Molecular biology DNA-Binding Proteins Cell culture 030220 oncology & carcinogenesis Tumor Suppressor Protein p53 Tumor Suppressor Proteins/genetics/ physiology DNA Damage |
| Zdroj: | Oncogene, Vol. 24, No 23 (2005) pp. 3726-3736 Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1208491 |
| Popis: | The BRCA1-associated RING domain protein BARD1 acts with BRCA1 in double-strand break repair and ubiquitination. BARD1 plays a role as mediator of apoptosis by binding to and stabilizing p53, and BARD1-repressed cells are resistant to apoptosis. We therefore investigated the mechanism by which BARD1 induces p53 stability and apoptosis. The apoptotic activity of p53 is regulated by phosphorylation. We demonstrate that BARD1 binds to unphosphorylated and serine-15 phosphorylated forms of p53 in several cell types and that the region required for binding comprises the region sufficient for apoptosis induction. In addition, BARD1 binds to Ku-70, the regulatory subunit of DNA-PK, suggesting that the mechanism of p53-induced apoptosis requires BARD1 for the phosphorylation of p53. Upregulation of BARD1 alone is sufficient for stabilization of p53 and phosphorylation on serine-15, as shown in nonmalignant epithelial cells and ovarian cancer cells, NuTu-19, which are defective in apoptosis induction and express aberrant splice variants of BARD1. Stabilization and phosphorylation of p53 in NuTu-19 cells, as well as apoptosis, can be induced by the exogenous expression of wild-type BARD1, suggesting that BARD1, by binding to the kinase and its substrate, catalyses p53 phosphorylation. |
| Databáze: | OpenAIRE |
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