Extending the functions of the homeotic transcription factor Cdx2 in the digestive system through nontranscriptional activities

Abstract

The homeoprotein encoded by the intestinal-specific Cdx2 gene is a major regulator of gut development and homeostasis, also involved in colon cancer as well as in intestinal-type metaplasias when it is abnormally expressed outside the gut. At the molecular level, structure/function studies have demonstrated that the Cdx2 protein is a transcription factor containing a conserved homeotic DNA-binding domain made of three alpha helixes arranged in a helix-turn-helix motif, preceded by a transcriptional domain and followed by a regulatory domain. The protein interacts with several thousand sites on the chromatin and widely regulates intestinal functions in stem/progenitor cells as well as in mature differentiated cells. Yet, this transcription factor also acts trough original nontranscriptional mechanisms. Indeed, the identification of novel protein partners of Cdx2 and also of a splicing variant revealed unexpected functions in the control of signaling pathways like the Wnt and NF-κB pathways, in double-strand break DNA repair and in premessenger RNA splicing. These novel functions of Cdx2 must be considered to fully understand the complexity of the role of Cdx2 in the healthy intestine and in diseases.

Keywords: Homeobox, Transcription, Signaling, DNA repair, RNA splicing, Intestine, Development, Cancer, Homeostasis

Core tip: The homeobox gene Cdx2 plays crucial functions in the gut, being the one determinant of intestinal identity during embryonic development, and then a key regulator of homeostasis of the gut epithelium throughout adulthood. It acts at the level of the stem/progenitor cells as well as in mature epithelial cells. Cdx2 is also important in digestive diseases, especially in colorectal cancer where it is thought to have a tumor suppressor role. In addition, it becomes abnormally expressed ectopically in non-intestinal organs, including gastric intestinal-type metaplasia and Barrett’s esophagus and their related adenocarcinomas, and even in leukemia. The homeoprotein Cdx2 primarily acts as a DNA-binding transcription factor. However, recent reports provide evidence for novel mechanisms of action that are transcription-independent. In this review, we summarize these new data that considerably extend the molecular potential of Cdx2 and open new questions and research area regarding the role of this homeoprotein in physiology and pathology.