Mechanisms of Bcr-Abl-mediated NF-κB/Rel activation
| Autor: | Gerd Munzert, Roland M. Schmid, Oliver G. Ottmann, Dieter Kirchner, Justus Duyster, Lothar Bergmann |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Transcriptional Activation
Oncogene Proteins v-rel Cancer Research Active Transport Cell Nucleus Fusion Proteins bcr-abl IκB kinase Protein Serine-Threonine Kinases Cell Line Mice Transactivation NF-KappaB Inhibitor alpha Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Genetics Animals Humans Phosphorylation Kinase activity Oncogene Proteins v-abl neoplasms Molecular Biology ABL Chemistry NF-kappa B I-Kappa-B Kinase DNA Cell Biology Hematology I-kappa B Kinase ras Proteins Cancer research I-kappa B Proteins REL Tyrosine kinase |
| Zdroj: | Experimental Hematology. 31:504-511 |
| ISSN: | 0301-472X |
| DOI: | 10.1016/s0301-472x(03)00069-9 |
| Popis: | Bcr-Abl constitutes a deregulated tyrosine kinase involved in the pathogenesis of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL). Although activation of the transcription factor NF-kappaB/Rel has been demonstrated, mechanisms of NF-kappaB/Rel activation by Bcr-Abl remain obscure. In this paper we demonstrate activation of NF-kappaB/Rel by Bcr-Abl and for the first time by v-Abl. Furthermore, we investigated mechanisms of NF-kappaB/Rel induction by Bcr-Abl and v-Abl. Both Bcr-Abl and v-Abl induced NF-kappaB/Rel DNA binding in Ba/F3 cells. DNA binding was a result of nuclear translocation of p65/RelA, whereas p65/RelA expression was unaffected. Nuclear translocation of p65/RelA is at least partially due to increased IkappaBalpha degradation, which is independent of IkappaB kinase (IKK) activity. IKK activity is not deregulated by Bcr-Abl and v-Abl. NF-kappaB/Rel transactivation was dependent on abl kinase activity but independent of Grb2 and Grb10 binding tobcr sequences. In addition, NF-kappaB/Rel activation was dependent on Ras activity. Primary CML blasts showed constitutive p65/RelA NF-kappaB/Rel DNA binding activity. Thus NF-kappaB/Rel represents a potential target for molecular therapies in CML. |
| Databáze: | OpenAIRE |
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