Novel Double-negative Feedback Loop between Adenomatous Polyposis Coli and Musashi1 in Colon Epithelia

Erick Spears,Kristi L Neufeld

doi:10.1074/jbc.c110.205922

Erick Spears, Kristi L Neufeld

Open Access

https://doi.org/10.1074/jbc.c110.205922

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Journal: The Journal of biological chemistry	Publication Date: Feb 1, 2011
Citations: 50	License type: cc-by

Affiliation: University of Kansas

Abstract

Loss of tumor suppressor adenomatous polyposis coli (APC) is thought to initiate the majority of all colorectal cancers. The predominant theory of colorectal carcinogenesis implicates stem cells as the initiating cells. However, relatively little is known about the function of APC in governing the homeostasis of normal intestinal stem cells. Here, we identify a novel double-negative feedback loop between APC and a translation inhibitor protein, Musashi1 (MSI1), in cultured human colonocytes. We show APC as a key factor in MSI1 regulation through Wnt signaling and identify APC mRNA as a novel target of translational inhibition by MSI1. We propose that APC/MSI1 interactions maintain homeostatic balance in the intestinal epithelium.

Highlights

Taining adenomatous polyposis coli (APC), Axin, and glycogen synthase kinase 3␤ binds to and phosphorylates ␤-catenin, leading to ubiquitination and degradation of ␤-catenin by the proteasome
Loss of APC Leads to Increased MSI1 Protein and mRNA in HCT116␤w Cells—In mice, inducible, intestine-specific loss of Apc led to a greater than 12-fold increase in Msi1 mRNA in intestinal tissue
APC mRNA and protein levels were both reduced in HCT116␤w cells transiently transfected with plasmids expressing short-hairpin RNA (shRNA) corresponding to the APC mRNA sequence (Fig. 1)

Summary

Introduction

Taining APC, Axin, and glycogen synthase kinase 3␤ binds to and phosphorylates ␤-catenin, leading to ubiquitination and degradation of ␤-catenin by the proteasome. Loss of Apc throughout the small intestine leads to expansion of undifferentiated, stem cell-like epithelium into the normally well differentiated villus compartment and a Ͼ12-fold increase in Msi1 mRNA [5]. APC mRNA and protein levels were both reduced in HCT116␤w cells transiently transfected with plasmids expressing shRNA corresponding to the APC mRNA sequence (Fig. 1).

Results

Conclusion