BCR-ABL down-regulates the DNA repair protein DNA-PKcs
| Autor: | Eric Deutsch, William Vainchenker, Ali G. Turhan, Jean Bourhis, Bassam Abdulkarim, François Eschwege, Setha Douc Rasy, Laurence Maggiorella, Aymeric Dugray, Radia M'Kacher, Sabine Vaganay, Elisabetta Marangoni |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
DNA Repair
Fusion Proteins bcr-abl Apoptosis DNA-Activated Protein Kinase Biochemistry chemistry.chemical_compound Mice Neuroblastoma hemic and lymphatic diseases Tumor Cells Cultured Enzyme Inhibitors Child DNA-PKcs In Situ Hybridization Fluorescence Tumor Stem Cell Assay Gene Expression Regulation Leukemic Reverse Transcriptase Polymerase Chain Reaction Nuclear Proteins Hematology Transfection DNA Neoplasm Tyrphostins DNA-Binding Proteins Leukemia Cysteine Endopeptidases Enzyme Induction Tyrosine kinase Oligopeptides Proteasome Endopeptidase Complex Recombinant Fusion Proteins Immunology In situ hybridization Biology Protein Serine-Threonine Kinases Multienzyme Complexes Leukemia Myelogenous Chronic BCR-ABL Positive Precursor B-Cell Lymphoblastic Leukemia-Lymphoma DNA Repair Protein medicine Animals Humans Protease Inhibitors Cell Biology medicine.disease Acetylcysteine chemistry Cancer research Blast Crisis DNA Chronic myelogenous leukemia |
| Zdroj: | Blood. 97(7) |
| ISSN: | 0006-4971 |
| Popis: | This study demonstrates in both stable and inducible BCR-ABL–expressing hematopoietic cells a down-regulation of the major mammalian DNA repair protein DNA-PKcs by BCR-ABL. Similar results were found in BCR-ABL CD34+ cells from patients with chronic myelogenous leukemia (CML). DNA-PKcs down-regulation is a proteasome-dependent degradation that requires tyrosine kinase activity and is associated with a marked DNA repair deficiency along with increased sensitivity to ionizing radiation. The conjunction of a major DNA repair deficiency and a resistance to apoptosis, both induced by BCR-ABL, provides a new mechanism to explain how secondary genetic alterations can accumulate in CML, eventually leading to blast crisis. The down-regulation of DNA-PKcs was reversible in CD34+ CML cells suggesting that this approach might offer a novel and powerful therapeutic strategy in this disease, especially to delay the blast crisis. |
| Databáze: | OpenAIRE |
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