Menin is a tumor suppressor protein mutated in patients with multiple endocrine 
neoplasia type 1. We show that menin is essential for canonical Wnt/beta-catenin 
signaling in cultured rodent islet tumor cells. In these cells, overexpression 
of menin significantly enhances TCF gene assay reporter activity in response to 
beta-catenin activation. Contrastingly, inhibition of menin expression with Men1 
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 beta-catenin, TCF3 (TCFL1), and weakly with TCF4 (TCFL2). Menin 
overexpression increases expression of the Wnt/beta-catenin downstream target 
gene Axin2, which is associated with increased H3K4 trimethylation of the Axin2 
gene promoter. Moreover, inhibition of menin expression by siRNA abrogates H3K4 
trimethylation and Axin2 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 3beta 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/beta-catenin signaling through a 
mechanism that eventually affects histone trimethylation of the downstream 
target gene Axin2, and activation of Wnt/beta-catenin signaling inhibits islet 
tumor cell proliferation.