BCR/ABL modulates protein phosphorylation associated with the etoposide-induced DNA damage response
| Autor: | Anthony D. Whetton, Andrew Pierce, Andrew J.K. Williamson, David N. Potier, Samuel J. Taylor, François Griaud, Elaine Spooncer |
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| Rok vydání: | 2012 |
| Předmět: |
Genome instability
Phosphosite DNA repair DNA damage Biophysics Fusion Proteins bcr-abl Apoptosis Biology Biochemistry Mice hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive Animals Phosphorylation Transcription factor BCR/ABL Etoposide ABL Gene Expression Regulation Leukemic Phosphoproteomics breakpoint cluster region Hemogen Nuclear Proteins Protein-Tyrosine Kinases Antineoplastic Agents Phytogenic MDC1 Cancer research NFκB DNA Damage |
| Zdroj: | Griaud, F, Williamson, A J K, Taylor, S, Potier, D N, Spooncer, E, Pierce, A & Whetton, A D 2012, ' BCR/ABL modulates protein phosphorylation associated with the etoposide-induced DNA damage response ', Journal of Proteomics, vol. 77, pp. 14-26 . https://doi.org/10.1016/j.jprot.2012.06.003 |
| ISSN: | 1876-7737 |
| DOI: | 10.1016/j.jprot.2012.06.003 |
| Popis: | BCR/ABL expression is the key characteristic of chronic myeloid leukaemia (CML). The progression of CML is associated with genomic instability. Systematic analysis of DNA damage signalling in the presence of BCR/ABL thus offers opportunities to identify mechanisms of leukaemic progression. We therefore undertook a quantitative phosphoproteomics study to test whether BCR/ABL expression could globally affect the response to genotoxic stress signalling. Etoposide-induced DNA damage was chosen and the concentration and time of exposure determined such that apoptosis was not associated with the study. More than 1100 phosphoentities were identified. BCR/ABL was shown to significantly alter the response to etoposide in many cases. These include sites on MDC1, a key component of DNA repair, and Hemogen. Hemogen is a transcriptional target of HOXB4 and GATA1, two transcription factors involved in haemopoietic development, and is overexpressed in acute myeloid leukaemia. To validate Hemogen phosphorylation, absolute quantification using an isotopomeric standard and selected reaction monitoring was performed. This revealed a strong correlation with isobaric tagging data and offering quantification at about 10 fmol per million cells. Furthermore we found that multiple protein phosphorylation changes mediated by BCR/ABL were connected to the increased activation of NFκB, a key survival transcription factor, after etoposide exposure. © 2012 Elsevier B.V. |
| Databáze: | OpenAIRE |
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