RIP140 increases APC expression and controls intestinal homeostasis and tumorigenesis.

Abstract

Deregulation of the Wnt/APC/β-catenin signaling pathway is an important consequence of tumor suppressor APC dysfunction. Genetic and molecular data have established that disruption of this pathway contributes to the development of colorectal cancer. Here, we demonstrate that the transcriptional coregulator RIP140 regulates intestinal homeostasis and tumorigenesis. Using Rip140-null mice and mice overexpressing human RIP140, we found that RIP140 inhibited intestinal epithelial cell proliferation and apoptosis. Interestingly, following whole-body irradiation, mice lacking RIP140 exhibited improved regenerative capacity in the intestine, while mice overexpressing RIP140 displayed reduced recovery. Enhanced RIP140 expression strongly repressed human colon cancer cell proliferation in vitro and after grafting onto nude mice. Moreover, in murine tissues and human cancer cells, RIP140 stimulated APC transcription and inhibited β-catenin activation and target gene expression. Finally, RIP140 mRNA and RIP140 protein levels were decreased in human colon cancers compared with those in normal mucosal tissue, and low levels of RIP140 expression in adenocarcinomas from patients correlated with poor prognosis. Together, these results support a tumor suppressor role for RIP140 in colon cancer.

• Authors: Marion Lapierre, Sandrine Bonnet, Caroline Bascoul-Mollevi, Imade Ait-Arsa, Stéphan Jalaguier, Maguy Del Rio, Michela Plateroti, Paul Roepman, Marc Ychou, Julie Pannequin, Frédéric Hollande, Malcolm Parker, Vincent Cavailles
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 5 Pg. 1899-913 (May 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24667635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APC protein, human
• Adaptor Proteins, Signal Transducing
• Adenomatous Polyposis Coli Protein
• NRIP1 protein, human
• Nuclear Proteins
• Nuclear Receptor Interacting Protein 1

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Adenomatous Polyposis Coli Protein (biosynthesis, genetics)
• Animals
• Apoptosis (genetics)
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Colonic Neoplasms (metabolism, pathology)
• Epithelial Cells (metabolism, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• Heterografts
• Homeostasis
• Humans
• Intestinal Mucosa (metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Mice, Nude
• Neoplasm Transplantation
• Nuclear Proteins (genetics, metabolism)
• Nuclear Receptor Interacting Protein 1