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EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association

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EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. / Paredes, Roberto; Schneider, Marion; Stevens, Adam et al.
In: Nucleic Acids Research, Vol. 46, No. 15, 01.06.2018, p. 7662-7674.

Research output: Contribution to journal › Article › peer-review

HarvardHarvard

Paredes, R, Schneider, M, Stevens, A, White, DJ, Williamson, AJK, Muter, J, Pearson, S, Kelly, JR, Connors, K, Wiseman, DH, Chadwick, JA, Löffler, H, Teng, HY, Lovell, S, Unwin, R, van de Vrugt, HJ, Smith, H, Kustikova, O, Schambach, A, Somervaille, TCP, Pierce, A, Whetton, AD & Meyer, S 2018, 'EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association', Nucleic Acids Research, vol. 46, no. 15, pp. 7662-7674. https://doi.org/10.1093/nar/gky536

APA

Paredes, R., Schneider, M., Stevens, A., White, D. J., Williamson, A. J. K., Muter, J., Pearson, S., Kelly, J. R., Connors, K., Wiseman, D. H., Chadwick, J. A., Löffler, H., Teng, H. Y., Lovell, S., Unwin, R., van de Vrugt, H. J., Smith, H., Kustikova, O., Schambach, A., ... Meyer, S. (2018). EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. Nucleic Acids Research, 46(15), 7662-7674. https://doi.org/10.1093/nar/gky536

CBE

Paredes R, Schneider M, Stevens A, White DJ, Williamson AJK, Muter J, Pearson S, Kelly JR, Connors K, Wiseman DH, et al. 2018. EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. Nucleic Acids Research. 46(15):7662-7674. https://doi.org/10.1093/nar/gky536

MLA

Paredes, Roberto et al. "EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association". Nucleic Acids Research. 2018, 46(15). 7662-7674. https://doi.org/10.1093/nar/gky536

VancouverVancouver

Paredes R, Schneider M, Stevens A, White DJ, Williamson AJK, Muter J et al. EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. Nucleic Acids Research. 2018 Jun 1;46(15):7662-7674. doi: 10.1093/nar/gky536

Author

Paredes, Roberto ; Schneider, Marion ; Stevens, Adam et al. / EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association. In: Nucleic Acids Research. 2018 ; Vol. 46, No. 15. pp. 7662-7674.

RIS

TY - JOUR

T1 - EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association

AU - Paredes, Roberto

AU - Schneider, Marion

AU - Stevens, Adam

AU - White, Daniel J

AU - Williamson, Andrew J K

AU - Muter, Joanne

AU - Pearson, Stella

AU - Kelly, James R

AU - Connors, Kathleen

AU - Wiseman, Daniel H

AU - Chadwick, John A

AU - Löffler, Harald

AU - Teng, Hsiang Ying

AU - Lovell, Simon

AU - Unwin, Richard

AU - van de Vrugt, Henri J

AU - Smith, Helen

AU - Kustikova, Olga

AU - Schambach, Axel

AU - Somervaille, Tim C P

AU - Pierce, Andrew

AU - Whetton, Anthony D

AU - Meyer, Stefan

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

U2 - 10.1093/nar/gky536

DO - 10.1093/nar/gky536

M3 - Article

VL - 46

SP - 7662

EP - 7674

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 15

ER -