EVI1 oncoprotein expression and CtBP1-association oscillate through the cell cycle
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SHORT COMMUNICATION
EVI1 oncoprotein expression and CtBP1-association oscillate through the cell cycle Roberto Paredes1,2 · Marion Schneider1,2 · Stella Pearson1,2 · Hsiang Yin Teng1,2 · James R. Kelly1,2 · Andrew Pierce1,2 · Tim C. P. Somervaille2,3 · Anthony D. Whetton1,2,4 · Stefan Meyer1,2,5,6 Received: 18 June 2020 / Accepted: 7 September 2020 © The Author(s) 2020
Abstract Aberrantly high expression of EVI1 in acute myeloid leukaemia (AML) is associated with poor prognosis. For targeted treatment of EVI1 overexpressing AML a more detailed understanding of aspects of spatiotemporal interaction dynamics of the EVI1 protein is important. EVI1 overexpressing SB1690CB AML cells were used for quantification and protein interaction studies of EVI1 and ΔEVI1. Cells were cell cycle-synchronised by mimosine and nocodazole treatment and expression of EVI1 and related proteins assessed by western blot, immunoprecipitation and immunofluorescence. EVI1 protein levels oscillate through the cell cycle, and EVI1 is degraded partly by the proteasome complex. Both EVI1 and ΔEVI1 interact with the co-repressor CtBP1 but dissociate from CtBP1 complexes during mitosis. Furthermore, a large fraction of EVI1, but not ΔEVI1 or CtBP1, resides in the nuclear matrix. In conclusion, EVI1- protein levels and EVI1-CtBP1 interaction dynamics vary though the cell cycle and differ between EVI1 and ΔEVI1. These data ad to the functional characterisation of the EVI1 protein in AML and will be important for the development of targeted therapeutic approaches for EVI1-driven AML. Keywords EVI1 · CtBP1 · Cell cycle · AML
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11033-020-05829-1) contains supplementary material, which is available to authorized users. * Stefan Meyer [email protected] 1
Stem Cell and Leukaemia Proteomics Laboratory, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
2
Manchester Academic Health Science Centre, National Institute for Health Research Biomedical Research Centre, Manchester, UK
3
Leukaemia Biology Group, CRUK Manchester Institute, Manchester, UK
4
Stoller Biomarker Discovery Centre, University of Manchester, Manchester, UK
5
Department of Paediatric Haematology and Oncology, Royal Manchester Children’s Hospital, Manchester, UK
6
c/o Academic Unit of Paediatric Oncology, Young Oncology Unit, The Christie NHS Foundation Trust, Christie Hospital, Wilmslow Road, Manchester M20 6XB, UK
Aberrantly high expression of EVI1 in acute myeloid leukaemia (AML) is commonly caused by chromosomal aberrations involving the MECOM (MDS-EVI1 complex) locus at 3q26 and associated with poor outcome [1, 2]. In AML, the overexpressed 1051 amino acid (aa) EVI1 protein can be co-expressed with the shorter ΔEVI1 isoform, which lacks a 324 aa sequence region (aa190-514), including the 6th and 7th zinc finger of the N-terminal zinc finger domain (Fig. 1a). The MDS-EVI1 isoform is us
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