Nuclear Receptors and Multiple Endocrine Neoplasia type 1 (MEN1)

Abstract

Multiple Endocrine Neoplasia type 1 (MEN1) is an inherited syndrome that is characterized by the occurrence of tumours of the parathyroid glands, gastroenteropancreatic tumours, pitui-tary gland adenomas, as well as adrenal adenomas and neuro-endocrine tumours, often at a young age. MEN1 tumours can be treated mostly by surgical methods. However, some tumours have malignant potential. Most patients require repeated surgery during their lifetime. MEN1 is caused by germ line mutations of the MEN1 gene. The MEN1 gene is a tumour suppressor gene. This means that both alleles in a cell need to be inactivated before a cell can develop into a tumour cell. The MEN1 gene encodes a protein termed menin. Menin is a nuclear protein that is involved in regulation of gene transcription, but possibly also DNA repair and replication. Menin can both be a co-activator and a co-repressor of gene transcription by recruiting proteins that modify histone proteins. Menin was found to be an integral component of a complex that has histone methyl-transferase activity directed at lysine 4 of histone H3 (H3K4). H3K4 trimethy-lation (H3K4me3) is associated with activation of transcription. To explore the function of menin and hence the pathogenesis of MEN1, we studied the amino acid sequence of menin. We found that menin contains a potential nuclear receptor interaction motif. The nuclear receptor family consists of 48 receptors for steroid hormones, vitamins A and D and other lipophilic agents. It is known that nuclear receptors can play a role in endocrine tumourigenesis. By protein interaction experiments, reporter assays and chromatin precipitation experiments, we found that menin can indeed bind to nuclear receptors and co-activate nuclear receptor function by recruiting H3K4-me3 activity to nuclear receptor target genes. Menin is also important for the biological function of nuclear receptors; in the absence of menin mouse embryonic fibroblasts fail to undergo PPARgamma dependent adipogenesis. In parathyroid adenomas from MEN1 patients, vitamin D receptor target genes are expressed at lower levels, suggesting that loss of menin could lead to decreased nuclear receptor activity. The connection of menin and nuclear receptors might offer new perspectives for future therapy for MEN1 patients.