부산대학교 도서관

Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type I (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MENI acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (Mu) family proteins in a histone methyltra nsferase complex including Ash2, Rbbps, and WDRS. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27kip1 and p18ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27ink4c and p18kip1 promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27kip1 and p18ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and Mu plays a central role in menin's activity as a tumor suppressor. [ABSTRACT FROM AUTHOR]