Fine-tuning and autoregulation of the intestinal determinant and tumor suppressor homeobox gene CDX2 by alternative splicing
Balbinot, Camille; Vanier, Marie; Armant, Olivier; Nair, Asmaa; Penichon, Julien; Soret, Christine; Martin, Elisabeth; Saandi, Thoueiba; Reimund, Jean Marie; Deschamps, Jacqueline; Beck, Felix; Domon-Dell, Claire; Gross, Isabelle M.; Duluc, Isabelle; Freund, Jean Noël
(2017) Cell Death and Differentiation, volume 24, issue 12, pp. 2173 - 2186
(Article)
Abstract
On the basis of phylogenetic analyses, we uncovered a variant of the CDX2 homeobox gene, a major regulator of the development and homeostasis of the gut epithelium, also involved in cancer. This variant, miniCDX2, is generated by alternative splicing coupled to alternative translation initiation, and contains the DNA-binding homeodomain but
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is devoid of transactivation domain. It is predominantly expressed in crypt cells, whereas the CDX2 protein is present in crypt cells but also in differentiated villous cells. Functional studies revealed a dominant-negative effect exerted by miniCDX2 on the transcriptional activity of CDX2, and conversely similar effects regarding several transcription-independent functions of CDX2. In addition, a regulatory role played by the CDX2 and miniCDX2 homeoproteins on their pre-mRNA splicing is displayed, through interactions with splicing factors. Overexpression of miniCDX2 in the duodenal Brunner glands leads to the expansion of the territory of these glands and ultimately to brunneroma. As a whole, this study characterized a new and original variant of the CDX2 homeobox gene. The production of this variant represents not only a novel level of regulation of this gene, but also a novel way to fine-tune its biological activity through the versatile functions exerted by the truncated variant compared to the full-length homeoprotein. This study highlights the relevance of generating protein diversity through alternative splicing in the gut and its diseases.
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Keywords: Gene expression, Molecular biology, Molecular Biology, Cell Biology
ISSN: 1350-9047
Publisher: Nature Publishing Group
Note: Funding Information: Acknowledgements. This work was supported by the INSERM (France) and the Fondation ARC (grants 3759 and 4872). CB, AN and CS were funded by the MRES (France). CB and CS were further supported by the Ligue Contre le Cancer, and TS by the Worldwide Cancer Research, UK (08-0199). We thank Dr. MA Birling and the Mouse Clinic Institute for generating the jojo-Flag-miniCdx2 mice, Professor MP Chenard (CHU de Strasbourg, France) for pathological evaluation of the mice, Dr. S Robine (CNRS, UMR 144, Institut Curie, Paris) for the VilCre mice, Professor B Chabot (Université de Sherbrooke) for the plasmids pHis-SRp30c and pHis-ASF/ SF2, and Dr. JF Launay (Inserm U682, Strasbourg) for help in C2T antibody purification. The data described here have been deposited in the GEO data base under the access code GSE89992. The Genbank accession number of human miniCDX2 is KJ531444. Publisher Copyright: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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