Data from Menin Promotes the Wnt Signaling Pathway in Pancreatic Endocrine Cells

Abstract

<div>Abstract<p>Menin is a tumor suppressor protein mutated in patients with multiple endocrine neoplasia type 1. We show that menin is essential for canonical Wnt/β-catenin signaling in cultured rodent islet tumor cells. In these cells, overexpression of menin significantly enhances <i>TCF</i> gene assay reporter activity in response to β-catenin activation. Contrastingly, inhibition of menin expression with <i>Men1</i> siRNA decreases TCF reporter gene activity. Likewise, multiple endocrine neoplasia type 1 disease associated missense mutations of menin abrogate the ability to increase TCF reporter gene activity. We show that menin physically interacts with proteins involved in the canonical Wnt signaling pathway, including β-catenin, TCF3 (TCFL1), and weakly with TCF4 (TCFL2). Menin overexpression increases expression of the Wnt/β-catenin downstream target gene <i>Axin2</i>, which is associated with increased H3K4 trimethylation of the <i>Axin2</i> gene promoter. Moreover, inhibition of menin expression by siRNA abrogates H3K4 trimethylation and <i>Axin2</i> gene expression. Based on these studies, we hypothesized that Wnt signaling could inhibit islet cell proliferation because loss of menin function is thought to increase endocrine tumor cell proliferation. TGP61 rodent islet tumor cells treated with a glycogen synthase kinase 3β inhibitor that increases Wnt pathway signaling had decreased cell proliferation compared with vehicle-treated cells. Collectively, these data suggest that menin has an essential role in Wnt/β-catenin signaling through a mechanism that eventually affects histone trimethylation of the downstream target gene <i>Axin2</i>, and activation of Wnt/β-catenin signaling inhibits islet tumor cell proliferation. (Mol Cancer Res 2008;6(12):1894–907)</p></div>