Abstract
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.
Highlights
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by the development of parathyroid hyperplasia, pancreatic islet cell tumors, and anterior pituitary endocrine tumors [1]
In cells expressing fluorescent epitope – tagged h-catenin, TCF3, and TCF4, menin overexpression did not affect the nuclear localization of these proteins (Fig. 1B). These data suggest that proteins important for canonical Wnt signaling are expressed in these cell lines, in particular the mouse islet tumor cell line TGP-61, and their expression is not altered by exogenous menin
Menin COOH-terminal truncation mutants lose their ability to interact with h-catenin and their ability to increase TCF gene reporter activity, which is consistent with a requirement for inactivation of Wnt signaling during islet tumor development
Summary
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by the development of parathyroid hyperplasia, pancreatic islet cell tumors, and anterior pituitary endocrine tumors [1]. Besides these classic tumors, several other endocrine and nonendocrine tumors may develop, including lipomas, dermatofibromas, collagenomas, ependymomas, meningiomas, schwannomas, carcinoids, adrenal cortical tumors, and thyroid tumors. MEN1 patients have truncation mutations and missense mutations that are predicted to inactivate menin function consistent with a tumor suppressor protein [3]. Similar to MEN1 patients, heterozygous knockout mice (Men1À/+) develop normally, but the adult mice eventually grow endocrine tumors [5]
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