Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by endocrine tumors of parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene encodes a nuclear protein called menin. In MEN1 carriers inactivating mutations give rise to a truncated product consistent with menin acting as a tumor suppressor gene. However, the role of menin in tumorigenesis and its physiological functions are not known. Here, we show that menin inactivation by antisense RNA antagonizes transforming growth factor type beta-mediated cell growth inhibition. Menin interacts with SMAD3, and antisense menin suppresses transforming growth factor type beta-induced and Smad3-induced transcriptional activity by inhibiting SMAD3/4-DNA binding at specific transcriptional regulatory sites. These results implicate a mechanism of tumorigenesis by menin inactivation.