The tumor suppressor protein menin interacts with NF-kappa B proteins and inhibits NF-kappa B-mediated transactivation

Multiple endocrine neoplasia type I is an autosomal dominant tumor syndrome . Manifestations include neoplasms of the parathyroid glands, entero pancre atic neuroendocrine cells, and the anterior pituitary gland. The MEN1 tumor suppressor gene encodes menin, a 610 amino acid nuclear protein without se quence homology to other proteins. To elucidate menin function, we used imm unoprecipitation to identify interacting proteins. The NF-kappaB proteins p 50, p52 and p65 were found to interact specifically and directly with menin in vitro and in vivo. The region of NF-kappaB proteins sufficient for bind ing to menin is the N-terminus. Furthermore, amino acids 305-381 of menin a re essential for this binding. Menin represses p65-mediated transcriptional activation on NF-kappaB sites in a dose-dependent and specific manner. Als o, PMA (phorbol 12-myristate 13-acetate)-stimulated NF-kappaB activation is suppressed by menin. These observations suggest that menin's ability to in teract with NF-kappaB proteins and its modulation of NF-kappaB transactivat ion contribute to menin's tumor suppressor function.