Loading...
EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.
Paredes, Roberto Schneider, Marion Stevens, A White, Daniel J Williamson, Andrew J K Muter, Joanne Pearson, Stella Kelly, James R Connors, Kathleen Wiseman, Daniel H
Paredes, Roberto
Schneider, Marion
Stevens, A
White, Daniel J
Williamson, Andrew J K
Muter, Joanne
Pearson, Stella
Kelly, James R
Connors, Kathleen
Wiseman, Daniel H
Citations
Altmetric:
Abstract
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.
Authors
Paredes, Roberto
Schneider, Marion
Stevens, A
White, Daniel J
Williamson, Andrew J K
Muter, Joanne
Pearson, Stella
Kelly, James R
Connors, Kathleen
Wiseman, Daniel H
Chadwick, John A
Löffler, H
Teng, Hsiang Ying
Lovell, S
Unwin, Richard D
van de Vrugt, H
Smith, H
Kustikova, O
Schambach, A
Somervaille, Tim C P
Pierce, Andrew
Whetton, Anthony D
Meyer, Stefan
Schneider, Marion
Stevens, A
White, Daniel J
Williamson, Andrew J K
Muter, Joanne
Pearson, Stella
Kelly, James R
Connors, Kathleen
Wiseman, Daniel H
Chadwick, John A
Löffler, H
Teng, Hsiang Ying
Lovell, S
Unwin, Richard D
van de Vrugt, H
Smith, H
Kustikova, O
Schambach, A
Somervaille, Tim C P
Pierce, Andrew
Whetton, Anthony D
Meyer, Stefan
Description
Date
2018-06-25
Publisher
Collections
Files
Keywords
Type
Article
Citation
EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. 2018, Nucleic Acids Res