Morgan, Rhys G, Ridsdale, Jenna, Payne, Megan, Heesom, Kate J, Wilson, Marieangela C, Davidson, Andrew, Greenhough, Alexander, Davies, Sara, Williams, Ann C, Blair, Allison, Waterman, Marian L, Tonks, Alex ![]() ![]() ![]() |
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Abstract
Canonical Wnt/β-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia patients; however, some patients exhibit little or no nuclear β-catenin even where cytosolic β-catenin is abundant. Control of the subcellular localization of β-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of β-catenin we carried out the first nuclear/cytoplasmic proteomic analysis of the β-catenin interactome in myeloid leukemia cells and identified putative novel β-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear β-catenin) versus Wnt-unresponsive cells (low nuclear β-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of β-catenin. The relative levels of nuclear LEF-1 and β-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed β-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and β-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first β-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear β-catenin level human myeloid leukemia
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine |
Publisher: | Ferrata Storti Foundation |
ISSN: | 0390-6078 |
Date of First Compliant Deposit: | 11 January 2019 |
Date of Acceptance: | 3 January 2019 |
Last Modified: | 23 Apr 2024 20:31 |
URI: | https://orca.cardiff.ac.uk/id/eprint/118305 |
Citation Data
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