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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 (MLL) 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 p27Kip1 and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c 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 MLL plays a central role in menin's activity as a tumor suppressor.

Original publication

DOI

10.1073/pnas.0408836102

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

18/01/2005

Volume

102

Pages

749 - 754

Keywords

Carrier Proteins, Cell Cycle Proteins, Cell Line, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p18, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, DNA-Binding Proteins, Gene Expression Regulation, Histone-Lysine N-Methyltransferase, Humans, Intracellular Signaling Peptides and Proteins, Myeloid-Lymphoid Leukemia Protein, Open Reading Frames, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogenes, Transcription Factors, Transcriptional Activation, Transfection, Tumor Suppressor Proteins