Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors

Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MILL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27(Kip1) and p18(Ink4c). Menin activates transcription by means of a mechanism involving recruitment of MILL to the p27(Kip1) and p18(Ink4c) promoters and coding regions. Loss of function of either MILL or menin results in down-regulation of p27(KiP1) and p18(Ink4c) expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MILL plays a central role in menin's activity as a tumor suppressor.