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Functional interplay between E2F1 and chemotherapeutic drugs defines immediate E2F1 target genes crucial for cancer cell death

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Abstract

The E2F1 transcription factor enhances apoptosis by DNA damage in tumors lacking p53. To elucidate the mechanism of a potential cooperation between E2F1 and chemotherapy, whole-genome microarrays of chemoresistant tumor cell lines were performed focusing on the identification of cooperation response genes (CRG). This gene class is defined by a synergistic expression response upon endogenous E2F1 activation and drug treatment. Cluster analysis revealed an expression pattern of CRGs similar to E2F1 mono-therapy, suggesting that chemotherapeutics enhance E2F1-dependent gene expression at the transcriptional level. Using this approach as a tool to explore E2F1-driven gene expression in response to anticancer drugs, we identified novel apoptosis genes such as the tumor suppressor TIEG1/KLF10 as direct E2F1 targets. We show that TIEG1/KLF10 is transcriptionally activated by E2F1 and crucial for E2F1-mediated chemosensitization of cancer cells. Our results provide a broader picture of E2F1-regulated genes in conjunction with cytotoxic treatment that allows the design of more rational therapeutics.

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Acknowledgments

The authors thank Katharina Fürst for technical assistance. We are grateful to Dr. Dirk Koczan for microarray hybridization. This work was supported by FORUN Grant 889040 from the Medical Faculty.

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  1. Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock, Schillingallee 69, 18057, Rostock, Germany

    David Engelmann, Susanne Knoll, Daniel Ewerth, Marc Steder, Anja Stoll & Brigitte M. Pützer

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  1. David Engelmann
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  2. Susanne Knoll
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Correspondence to Brigitte M. Pützer.

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Engelmann, D., Knoll, S., Ewerth, D. et al. Functional interplay between E2F1 and chemotherapeutic drugs defines immediate E2F1 target genes crucial for cancer cell death. Cell. Mol. Life Sci. 67, 931–948 (2010). https://doi.org/10.1007/s00018-009-0222-0

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