Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation.
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.
Dreijerink
Koen Ma
KM
Department of Internal Medicine and Endocrinology, University Medical Center Utrecht, The Netherlands.
Höppener
Jo Wm
JW
Timmers
Ht Marc
HM
Lips
Cornelis Jm
CJ
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
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