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  • Oncogenomics
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A microarray-based, integrated approach to identify novel regulators of cancer drug response and apoptosis

Oncogene volume 21, pages 8361–8371 (2002)Cite this article

Abstract

DNA microarrays are powerful tools for the analysis of gene expression on a genomic scale. The importance of individual regulatory events for the process under study can however not be deduced unequivocally without additional experiments. We devised a strategy to identify central regulators of cancer drug responses by combining the results of microarray experiments with efficient methods for phenotypic testing of candidate genes. We exposed murine FL5.12 pro-B cells to cisplatin, camptothecin, methotrexate or paclitaxel, respectively and analysed the patterns of gene expression with cDNA microarrays. Drug-specific regulatory events as well as intersections between different apoptotic pathways, including previously studied responses to staurosporine and interleukin-3 (IL-3) deprivation, were identified. Genes shared by at least three pathways were chosen for further analysis. Ectopic expression of three such genes, TEAP, GP49B, and Lipin1 was found to have an anti-proliferative effect on pro-B cells. Interestingly, we identified hemoglobin alpha as a strong pro-apoptotic regulator. While hemoglobin-expressing cells were growing normally in the presence of IL-3, they displayed accelerated apoptosis with similar kinetics as Bax overexpressing cells upon IL-3 removal. The pro-apoptotic effect of hemoglobin was suppressed by Bcl-2 and was characterized by enhanced stimulation of caspase activity.

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Acknowledgements

We thank Marion Kamke and Brigitte Besenreuther for excellent technical assistance.

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Authors and Affiliations

  1. Molecular and Cellular Biology Senior Scientific Expert Laboratory, Novartis Pharma AG, CH-4002, Basel, Switzerland

    Benoit Pierrat, Alexandros Xynos, Karin Brecht, Marjo Simonen & Jutta Heim

  2. Oncology Research, Novartis Pharma AG, CH-4002, Basel, Switzerland

    Arndt Brachat & Adrian Brüngger

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  1. Arndt Brachat
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  2. Benoit Pierrat
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Correspondence to Jutta Heim.

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Brachat, A., Pierrat, B., Xynos, A. et al. A microarray-based, integrated approach to identify novel regulators of cancer drug response and apoptosis. Oncogene 21, 8361–8371 (2002). https://doi.org/10.1038/sj.onc.1206016

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