Transcription Regulation of the Multiple Endocrine Neoplasia Type 1 Gene in Human and Mouse

Abstract

Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant tumor syndrome, with the presence of tumors in parathyroid, pancreatic, and anterior pituitary. The tumor suppressor gene MEN1, located on chromosome 11q13, encodes a 610 amino acid, 68-kDa protein, menin. Menin is conserved among species but has no similarity with any known protein. To investigate how the expression is regulated in both man and mouse, we assayed a greater than 1-kb region upstream of the second exon for promoter activity in luciferase reporter vectors. The basic promoter was located closely upstream the most commonly expressed first exon. The region further upstream modified the activity. Repetitive elements of the short interspersed/Alu type covered the entire human upstream regulatory region and were the only apparent motif in common with its murine ortholog. Previous studies have indicated a compensatory induction of the second allele because of inactivation of the first allele. We found that overexpression of menin in an inducible cell culture system down-regulated the proximal promoter. In response to down-regulation of MEN1 expression by RNA interference, the regulatory region activated the promoter in a compensatory manner. Our data confirm that the expression of the MEN1 gene is regulated by a feedback from its product menin.

Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients

“…24 Moreover, in an inducible cell culture system, an over-expression of menin has been reported to down-regulate the MEN1 proximal promoter, whereas the silencing of MEN1 mRNA expression activated the promoter in a compensatory manner. 29 Although the EcR-293 cell lines (human embryo kidney 293) used did not derive from tissues that are not usually affected by the MEN1 syndrome and, mainly, any increase of the endogenous MEN1 mRNA was never shown, the authors proposed a transcriptional feedback exerted by menin on MEN1 gene expression. 24,29 In this study, the simultaneous analysis of both MEN1 mRNA and menin expression in MEN1 primary fibroblast cultures made possible to propose a mechanism of compensation for allelic mutation by up-regulating the expression of menin active at a post-transcriptional level, as menin compensation did not require an increase of MEN1 mRNA transcription.…”

“…29 Although the EcR-293 cell lines (human embryo kidney 293) used did not derive from tissues that are not usually affected by the MEN1 syndrome and, mainly, any increase of the endogenous MEN1 mRNA was never shown, the authors proposed a transcriptional feedback exerted by menin on MEN1 gene expression. 24,29 In this study, the simultaneous analysis of both MEN1 mRNA and menin expression in MEN1 primary fibroblast cultures made possible to propose a mechanism of compensation for allelic mutation by up-regulating the expression of menin active at a post-transcriptional level, as menin compensation did not require an increase of MEN1 mRNA transcription. In fact, for the enhancement of menin-oncosuppressor expression, the integrity of wildtype MEN1 mRNA, but not its transcriptional increase, is needed.…”

“…28 In response to down-regulation of MEN1 expression by RNA interference, the regulatory region activated the promoter in a compensatory manner. 29 These data prompted the authors to speculate that the expression of the MEN1 gene is regulated through a feedback mechanism from its product menin. 29 In this study, we focused on the analysis of the in vitro expression of MEN1 mRNA and menin in primary cell cultures from both healthy fibroblasts and fibroblasts obtained from MEN1 patients using RNA silencing approaches.…”

“…29 These data prompted the authors to speculate that the expression of the MEN1 gene is regulated through a feedback mechanism from its product menin. 29 In this study, we focused on the analysis of the in vitro expression of MEN1 mRNA and menin in primary cell cultures from both healthy fibroblasts and fibroblasts obtained from MEN1 patients using RNA silencing approaches. We showed, for the first time, an RNAbinding activity of menin that may modulate the mechanism of induction of menin-oncosuppressor expression and its function in transcriptional regulation.…”

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis

“…Intriguingly, mice with liver-specific loss of menin did not develop tumors (Scacheri et al 2004). The expression levels of menin in lymphoblastic cell lines derived from MEN1 patients did not differ from healthy controls (Wautot et al 2000) and downregulation of menin could activate the MEN1 promoter in a compensatory manner in nonendocrine cell lines (Zablewska et al 2003). However, it has been suggested that menin haploinsufficiency through loss of one Men1 allele contributes to pNET development in mice , Lejonklou et al 2012.…”