The balance of TCF7L2 variants with differential activities in Wnt-signaling is regulated by lithium in a GSK3{beta}-independent manner
- Department of Clinical Sciences, University of Kentucky, Lexington, KY (United States)
- Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University School of Medicine, Washington, DC (United States)
Research highlights: {yields} Identification of a novel effect of lithium on the expression of TCF7L2 RNA isoforms and protein variants. {yields} The extent of lithium-induced TCF7L2 form switch mirrors cell responsiveness to Wnt/{beta}-catenin signaling. {yields} Demonstration that lithium has dual GSK3{beta}-dependent and -independent effects on TCF7L2 expression. {yields} Demonstration that TCF7L2 expression is repressed by the transcriptionally active TCF7L2E form. {yields} Evidence for a lithium-induced de-repression mechanism of TCF7L2 expression via TCF7L2 variant switch. -- 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 GSK3{beta} 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 GSK3{beta}-dependent up-regulation and a GSK3{beta}-independent modulation of RNA splicing. TCF7L2E-long forms display a repressor activity on TCF7L2-promoter reporters and lithium induces a decrease of the endogenous TCF7L2 forms bound to native TCF7L2-promoter chromatin at two novel distal TCF7-binding sites. Altogether our data reveal a lithium-induced RNA switch favoring the expression of TCF7L2-short forms, which results in a transcriptional de-repression of lithium target genes negatively regulated by TCF7L2-long forms, like TCF7L2, and thus to an amplification of Wnt-signaling in responsive cells.
- OSTI ID:
- 22202744
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 399, Issue 2; Other Information: Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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