The balance of TCF7L2 variants with differential activities in Wnt-signaling is regulated by lithium in a GSK3beta-independent manner.

Biochemical and Biophysical Research Communications
Ian StruewingCatherine D Mao

Abstract

TCF7L2 transcription factor is a downstream effector of the canonical Wnt/beta-catenin signaling, which controls cell fate and homeostasis. However, the complexity of TCF7L2 expression with numerous mRNA isoforms coding for proteins with distinct N- and C-termini allows variability in TCF7L2 functions and regulations. Here, we show that although TCF7L2 mRNA isoforms distinguish fetal, immortalized and adult differentiated endothelial cells (EC), they cannot explain the lack of significant beta-catenin/TCF7 activities in ECs. Lithium, a Wnt-signaling activator, increases TCF7L2 mRNA levels and induces an RNA isoform switch favoring the expression of TCF7L2-short forms lacking the C-termini domains. Although the latter occurs in different cell types, its extent depends on the overall increase of TCF7L2 transcription, which correlates with cell responsiveness to Wnt/beta-catenin signaling. While GSK3beta down-regulation increases TCF7L2 expression, there is no concomitant change in TCF7L2 mRNA isoforms, which demonstrate the dual effects of lithium on TCF7L2 expression via a GSK3beta-dependent up-regulation and a GSK3beta-independent modulation of RNA splicing. TCF7L2E-long forms display a repressor activity on TCF7L2-promoter rep...Continue Reading

References

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May 2, 2009·The Journal of Biological Chemistry·Ian T StruewingCatherine D Mao
Jul 16, 2009·Human Molecular Genetics·Ludmila Prokunina-OlssonJennifer L Hall
Feb 2, 2010·Nature Genetics·Kyle J GaultonJorge Ferrer

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