title: Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation.
abstract: 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 beta 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.
authors.affiliation: Department of Internal Medicine and Endocrinology, University Medical Center Utrecht, The Netherlands.
authors.forename: Koen Ma
authors.initials: KM
authors.lastname: Dreijerink
authors.forename: Jo Wm
authors.initials: JW
authors.lastname: Höppener
authors.forename: Ht Marc
authors.initials: HM
authors.lastname: Timmers
authors.forename: Cornelis Jm
authors.initials: CJ
authors.lastname: Lips
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D005786:Gene Expression Regulation; D016758:Genes, jun / Q000502:physiology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D018761:Multiple Endocrine Neoplasia Type 1 / Q000175:diagnosis / Q000235:genetics*; D016328:NF-kappa B / Q000502:physiology; D011496:Protein Methyltransferases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D002843:Chromatin; C105373:MEN1 protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase