γ-Catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of β-catenin

Morgan, Rhys G., Pearn, Lorna, Liddiard, Kate ORCID: https://orcid.org/0000-0002-0953-1997, Pumford, Sara Louise, Burnett, Alan Kenneth, Tonks, Alex ORCID: https://orcid.org/0000-0002-6073-4976 and Darley, Richard Lawrence ORCID: https://orcid.org/0000-0003-0879-0724 2013. γ-Catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of β-catenin. Leukemia 27 (2) , pp. 336-343. 10.1038/leu.2012.221

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Abstract

Canonical Wnt signaling regulates the transcription of T-cell factor (TCF)-responsive genes through the stabilization and nuclear translocation of the transcriptional co-activator, β-catenin. Overexpression of β-catenin features prominently in acute myeloid leukemia (AML) and has previously been associated with poor clinical outcome. Overexpression of γ-catenin mRNA (a close homologue of β-catenin) has also been reported in AML and has been linked to the pathogenesis of this disease, however, the relative roles of these catenins in leukemia remains unclear. Here we report that overexpression and aberrant nuclear localization of γ-catenin is frequent in AML. Significantly, γ-catenin expression was associated with β-catenin stabilization and nuclear localization. Consistent with this, we found that ectopic γ-catenin expression promoted the stabilization and nuclear translocation of β-catenin in leukemia cells. β-Catenin knockdown demonstrated that both γ- and β-catenin contribute to TCF-dependent transcription in leukemia cells. These data indicate that γ-catenin expression is a significant factor in the stabilization of β-catenin in AML. We also show that although normal cells exclude nuclear translocation of both γ- and β-catenin, this level of regulation is lost in the majority of AML patients and cell lines, which allow nuclear accumulation of these catenins and inappropriate TCF-dependent transcription.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	Wnt signaling; catenin; TCF/LEF; acute myeloid leukemia; nuclear translocation; transcription
Publisher:	Nature Publishing Group
ISSN:	0887-6924
Last Modified:	08 Jan 2024 07:34
URI:	https://orca.cardiff.ac.uk/id/eprint/37229

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