Home > Publications database > EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. > print

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024 7 _ |a 10.1093/nar/gky536
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082 _ _ |a 540
100 1 _ |a Paredes, Roberto
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245 _ _ |a EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.
260 _ _ |a Oxford
|c 2018
|b Oxford Univ. Press44364
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520 _ _ |a The transcriptional regulator EVI1 has an essential role in early hematopoiesis and development. However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors. To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. In the presence of genotoxic stress EVI1-WT (SQS), but not site mutated EVI1-AQA was able to maintain transcriptional patterns and transformation potency, while under standard conditions carboxy-terminal mutation had no effect. Maintenance of hematopoietic progenitor cell clonogenic potential was profoundly impaired with EVI1-AQA compared with EVI1-WT, in particular in the presence of genotoxic stress. Exploring mechanistic events underlying these observations, we showed that after genotoxic stress EVI1-WT, but not EVI1-AQA increased its level of association with its functionally essential interaction partner CtBP1, implying a role for ATM in regulating EVI1 protein interactions via phosphorylation. This aspect of EVI1 regulation is therapeutically relevant, as chemotherapy-induced genotoxicity might detrimentally sustain EVI1 function via stress response mediated phosphorylation, and ATM-inhibition might be of specific targeted benefit in EVI1-overexpressing malignancies.
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700 1 _ |a Schneider, Marion
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700 1 _ |a Stevens, Adam
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700 1 _ |a White, Daniel J
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700 1 _ |a Williamson, Andrew J K
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700 1 _ |a Muter, Joanne
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700 1 _ |a Pearson, Stella
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700 1 _ |a Kelly, James R
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700 1 _ |a Connors, Kathleen
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700 1 _ |a Wiseman, Daniel H
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700 1 _ |a Löffler, Harald
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700 1 _ |a Teng, Hsiang Ying
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700 1 _ |a Lovell, Simon
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700 1 _ |a Unwin, Richard
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700 1 _ |a van de Vrugt, Henri J
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700 1 _ |a Smith, Helen
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700 1 _ |a Kustikova, Olga
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700 1 _ |a Schambach, Axel
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700 1 _ |a Somervaille, Tim C P
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700 1 _ |a Pierce, Andrew
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700 1 _ |a Whetton, Anthony D
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700 1 _ |a Meyer, Stefan
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773 _ _ |a 10.1093/nar/gky536
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