Menin promotes the Wnt signaling pathway in pancreatic endocrine cells.
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.
Chen
Gao
G
David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095-6904, USA.
A
Jingbo
J
Wang
Min
M
Farley
Steven
S
Lee
Lung-Yi
LY
Lee
Lung-Ching
LC
Sawicki
Mark P
MP
D007516:Adenoma, Islet Cell / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D060466:Axin Protein; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C491761:AXIN2 protein, human; C111729:Axin2 protein, mouse; C495270:CTNNB1 protein, human; C105373:MEN1 protein, human; C484898:Men1 protein, mouse; C407909:TCF3 protein, human; C532096:TCF4 protein, human