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Published on: November 21, 2015
RIP140 Represses Intestinal Paneth Cell Differentiation and Interplays with SOX9 Signaling in Colorectal Cancer
Antoine Gleizes1, Mouna Triki1, Sandrine Bonnet1
1IRCM-Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier, CNRS, 208 rue des Apothicaires, F-34298 Montpellier, France.
Abstract:
RIP140 is a major transcriptional coregulator of gut homeostasis and tumorigenesis through the regulation of Wnt/APC signaling. Here, we investigated the effect of RIP140 on Paneth cell differentiation and its interplay with the transcription factor SOX9. Using loss of function mouse models, human colon cancer cells, and tumor microarray data sets we evaluated the role of RIP140 in SOX9 expression and activity using RT-qPCR, immunohistochemistry, luciferase reporter assays, and GST-pull down. We first evidence that RIP140 strongly represses the Paneth cell lineage in the intestinal epithelium cells by inhibiting Sox9 expression. We then demonstrate that RIP140 interacts with SOX9 and inhibits its transcriptional activity. Our results reveal that the Wnt signaling pathway exerts an opposite regulation on SOX9 and RIP140. Finally, the levels of expression of RIP140 and SOX9 exhibit a reverse response and prognosis value in human colorectal cancer biopsies. This work highlights an intimate transcriptional cross-talk between RIP140 and SOX9 in intestinal physiopathology.
Insights
RIP140 represses Paneth cell differentiation by inhibiting SOX9 expression and activity. This RIP140-SOX9 cross-talk impacts gut homeostasis and colorectal cancer progression.
Area of Science:
- Molecular Biology
- Gastroenterology
- Oncology
Background:
- RIP140 is a key regulator of gut homeostasis and tumorigenesis via Wnt/APC signaling.
- Paneth cells are crucial for intestinal epithelium integrity and function.
- The interplay between RIP140 and SOX9 in Paneth cell differentiation is not well understood.
Purpose of the Study:
- To investigate the role of RIP140 in Paneth cell differentiation.
- To elucidate the interaction between RIP140 and the transcription factor SOX9.
- To determine the clinical significance of RIP140 and SOX9 in colorectal cancer.
Main Methods:
- Loss-of-function mouse models and human colon cancer cells were utilized.
- Gene expression and protein interactions were analyzed using RT-qPCR, immunohistochemistry, and GST-pull down assays.
- Transcriptional activity was assessed via luciferase reporter assays.
Main Results:
- RIP140 was found to repress Paneth cell lineage by inhibiting SOX9 expression.
- RIP140 directly interacts with SOX9, suppressing its transcriptional activity.
- The Wnt signaling pathway differentially regulates SOX9 and RIP140.
- RIP140 and SOX9 expression levels show an inverse correlation and prognostic value in colorectal cancer.
Conclusions:
- RIP140 acts as a repressor of Paneth cell differentiation through SOX9 inhibition.
- A significant cross-talk exists between RIP140 and SOX9 in intestinal pathophysiology.
- The RIP140-SOX9 axis represents a potential therapeutic target for colorectal cancer.
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