Nuclear-cytoplasmic shuttling of menin regulates nuclear translocation of {beta}-catenin.

Menin, which is encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor and transcriptional regulator. Menin controls proliferation and apoptosis of cells, especially pancreatic beta cells. We have found that menin contains two functional nuclear export signals and that there is nuclear accumulation of beta-catenin in Men1-null mouse embryonic fibroblasts and insulinoma tissues from beta-cell-specific Men1 knockout mice. It is reported that the deregulation of Wnt/beta-catenin signaling caused by inactivation of tumor suppressors results in abnormal development or tumorigenesis. We further revealed that overexpression of menin reduces beta-catenin nuclear accumulation and its transcriptional activity. Menin is able to directly interact with beta-catenin and carry beta-catenin out of the nucleus via nuclear-cytoplasmic shuttling in a CRM1-dependent manner. These results imply that menin may control cell proliferation through suppression of Wnt/beta-catenin signaling.