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TCF-4 isoforms absent in TCF-4 mutated MSI-H colorectal cancer cells colocalize with nuclear CtBP and repress TCF-4-mediated transcription

Abstract

TCF-4 is the main effector of the Wnt/Wingless signalling pathway. As with other TCF/LEF factors, numerous alternative splicings at its 3′ end affect its expression. Such a mechanism leads to the synthesis of numerous TCF-4 isoforms among which some contain binding domains for CtBP, an ubiquitous transcriptional corepressor. Of interest, we described a frequent TCF-4 frameshift mutation in mismatch-repair deficient colorectal cancers (MSI-H cancers) that leads to the selective loss of TCF-4 isoforms with CtBP binding abilities. We provide here data that argue for a partial colocalization of CtBP with TCF-4 isoforms containing CtBP binding domains in cellulo, and for a functional role of CtBP in repressing TCF-4 mediated transcription. We also demonstrate that such a colocalization is not observed in MSI-H colorectal cancer cells that harbour the TCF-4 frameshift mutation, and that CtBP is not able to repress TCF-4-mediated transcription in this context. Taken together, our results strongly suggest that CtBP would play a role in regulating TCF-4 mediated transcription upon its binding with some TCF-4 isoforms encoded by alternatively spliced mRNA. They also suggest a role for TCF-4 frameshift mutation during MSI-H colorectal tumour progression, by regulating the relative proportion of the different TCF-4 isoforms.

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Acknowledgements

We thank Andreas Jung, Bert Vogelstein and Bohdan Wasylyk for the generous gift of expression vectors pΔ45βcatenin, pTCF-4(A)9, pTCF-4(A)8 and pCtBP. We also thank Barry Iacopetta for critical reading of the manuscript. This work was partly supported by grants from the Association Nationale de Recherche sur le SIDA (credit number 03/162) and from the Association pour la Recherche contre le Cancer (credit number 3301). JEB was recipient of a fellowship from the Ministère Français de la Recherche (MRT). PCD was recipient of a fellowship from the Association pour la Recherche contre le Cancer.

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Cuilliere-Dartigues, P., El-Bchiri, J., Krimi, A. et al. TCF-4 isoforms absent in TCF-4 mutated MSI-H colorectal cancer cells colocalize with nuclear CtBP and repress TCF-4-mediated transcription. Oncogene 25, 4441–4448 (2006). https://doi.org/10.1038/sj.onc.1209471

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