Mechanisms of Disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation

Multiple endocrine neoplasia type 1 can be caused by mutations in the gene encoding menin. By interacting with both transcription factors and histone-protein modifying factors, menin can activate or repress gene expression, and—as detailed here—specific pathways affected by menin have been identified. This offers hope for new screening and therapeutic strategies. Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by tumors of the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as by neuroendocrine carcinoid tumors, often at a young age. Causal to the syndrome are germline mutations of the MEN1 tumor-suppressor gene. Identification of gene-mutation carriers has enabled presymptomatic diagnosis and treatment of MEN1-related lesions. The product of the MEN1 gene is the nuclear protein menin. Recent observations indicate several functions for menin in the regulation of transcription, serving either as a repressor or as an activator: menin interacts with the activator-protein-1-family transcription factor JunD, changing it from an oncoprotein into a tumor-suppressor protein, putatively by recruitment of histone deacetylase complexes; menin maintains transforming growth factor β mediated signal transduction involved in parathyroid hormone and prolactin gene expression; and menin is an integral component of histone methyltransferase complexes. In this capacity menin is a regulator of expression of the cyclin-dependent-kinase inhibitors p18INK4C and p27Kip1; furthermore, menin serves as a co-activator of estrogen receptor mediated transcription, by recruiting methyltransferase activity to lysine 4 of histone 3 at the estrogen responsive TFF1(pS2) gene promoter. We propose that menin links transcription-factor function to histone-modification pathways and that this is crucial for MEN1 tumorigenesis. Understanding the molecular pathology of MEN1 tumorigenesis will lead to new therapeutic strategies. Key Points Multiple endocrine neoplasia type 1 is caused by germline mutations of the gene that encodes a protein termed menin Menin is a nuclear protein involved in the regulation of gene expression at the level of transcription Menin is a link between chromatin-modifying protein complexes and transcription regulation Understanding the mechanism of action for menin will eventually provide targets for future therapeutic strategies