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

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.

Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion

“…As a negative regulator in the Wnt signaling pathway, Apc inhibits Msi-1 transcription (Rezza et al, 2010;Spears and Neufeld, 2011). Conversely, Msi-1 binds to Apc mRNA and blocks translation (Spears and Neufeld, 2011). Although in vitro evidence supports an integral role for the Apc and Msi-1 negative-feedback loop in gene regulation, the existence of this Apc and Msi-1 antagonistic relationship in intestinal tissue is unknown.…”

“…When Apc is conditionally deleted in intestines of adult mice, one of the most highly upregulated transcripts encodes the RNA-binding protein Musashi-1 (Msi-1) (Sansom et al, 2004). Intestinal polyps in mice with germline Apc mutations (Apc Min ) also show an upregulation of Msi-1 (Potten et al, 2003) and Msi-1 has been identified as a Wnt target gene (Rezza et al, 2010;Spears and Neufeld, 2011).…”

“…Our previous work revealed a mutually repressive feedback loop between Apc and Msi-1 in cultured cells (Spears and Neufeld, 2011). As a negative regulator in the Wnt signaling pathway, Apc inhibits Msi-1 transcription (Rezza et al, 2010;Spears and Neufeld, 2011).…”

“…As a negative regulator in the Wnt signaling pathway, Apc inhibits Msi-1 transcription (Rezza et al, 2010;Spears and Neufeld, 2011). Conversely, Msi-1 binds to Apc mRNA and blocks translation (Spears and Neufeld, 2011).…”

New insights from animal models of colon cancer: inflammation control as a new facet on the tumor suppressor APC gem

“…145 A potential link between Notch signaling and APC is that APC is in a double negative feedback loop with the transcription inhibitor Msi-1. 146 Msi-1 activates Notch signaling by inhibiting the Notch repressor, Numb. 147 In cases of Apc mutation, Msi-1 is upregulated; activating Notch signaling.…”