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

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

PROVIDER: PRJNA475639 | ENA |

REPOSITORIES: ENA

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

Project description: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 posttranslational 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.

2018-06-12 | GSE115643 | GEO

EVI1-phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal

Project description:The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high EVI1 expression has very poor prognosis. To investigate effects of posttranslational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436). EVI1-WT (wild type), with S436 available for phosphorylation, but not EVI1-S436A, conferred haematopoietic progenitor cell self-renewal associated with significantly higher organised transcriptional patterns. In silico modelling of EVI1-S436 phosphorylation showed affinity reduction to CtBP1, and EVI1-WT showed reduced interaction with CtBP1 compared with EVI1-S463A. The target the motif harbouring S436 is targeted by CDK2 and CDK3 kinases, which both interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared to EVI1-S436A, and a hypo-methylated cell population associated with EVI1-WT expression is not maintained with EVI1-S436A. These data point to a role of the EVI1-S436 phosphorylation for directing functional protein interactions for haematopoietic self-renewal. Targeting EVI1-S436 phosphorylation may benefit therapy for EVI1-driven leukaemia.

2020-11-01 | GSE157315 | GEO

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

Project description: Not available

| S-EPMC6125627 | biostudies-literature

Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2

Project description:Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable with current chemotherapy regimens. Insight into the mechanism by which EVI1 drives myeloid transformation is needed to target EVI1 in those leukemias. Here we demonstrate recurrent interaction of CTBP1/2 with a unique PLDLS motif in EVI1, which is indispensable for leukemic transformation of 3q26/MECOM rearranged AML. A PLDLS competitor construct outcompetes EVI1 to CTBP1/2 binding and inhibits AML proliferation in xenotransplant models. This proof-of-concept study opens the possibility to target one of the most incurable forms of AML using specific inhibitors directed to EVI1/CTBP1/2 interaction. Our findings have important implications for other tumour types with aberrant expression of EVI1 or other oncogenic transcription factors that also depend on CTBP1/2 interaction.

2023-07-13 | PXD043333 | Pride

Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2 [ChIP-Seq]

2023-07-12 | GSE236010 | GEO

Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2 [RNA-seq]

2023-09-30 | GSE243620 | GEO

EVI1-phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal

Project description:EVI1-phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal

| PRJNA660816 | ENA

EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal.

Project description: Not available

| S-EPMC7576810 | biostudies-literature

Effects of PSF and CTBP1-AS knockdown in prostate cancer cell lines

Project description:Prostate cancer is the most common cancer in men and Androgen receptor (AR) downstream signalings promote prostate cancer cell proliferation. We identified androgen-regulated long non-coding RNA, CTBP1-AS, located in the antisese region of CTBP1 gene. CTBP1-AS activate AR signaling by epigenetically repress AR-associated cofactors such as CTBP1 by interactign with RNA-binding protein PSF and recruiting HDAC complex to the target promoters. In order to investigate the CTBP1-AS and PSF function in prostate cancer cells, we performed gene expression in AR-positive prostate cancer cell lines after siPSF or siCTBP1-AS treatment. We also treated cells with vehicle or androgen to analyzed the effects of CTBP1-AS and PSF on AR function. Observation of androgen dependent gene expression changes after treatmet with siRNAs targeting CTBP1-AS and PSF with microarray.

2014-01-01 | E-GEOD-44264 | biostudies-arrayexpress

The whole transcriptome expression profiling of human SKOV3 comparison between control and CtBP1 KD, ctbp2 KD and CTBP1/2 DKD.

Project description:To discover the regulatory role of CTBP1/2 in high grade serous ovarian cancer, The full cDNA was extracted from SKOV3 shRNA control and CtBP1/2 knockdown and then compared the expression profiles of them to discovery the key functions and pathways regulated by CtBP1/2..

2022-05-21 | GSE175425 | GEO

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