miR-24 regulates menin in the endocrine pancreas

Abstract

Vijayaraghavan J, Maggi EC, Crabtree JS. miR-24 regulates menin in the endocrine pancreas. Am J Physiol Endocrinol Metab 307: E84 -E92, 2014. First published May 13, 2014; doi:10.1152/ajpendo.00542.2013.-Menin, the product of the MEN1 gene, functions as a tumor suppressor and was first identified in 1997 due to its causative role in the endocrine tumor disorder multiple endocrine neoplasia, type 1 (MEN1). More recently, menin has been identified as a key player in pancreatic islet biology with the observation of an inverse relationship between menin levels and pancreatic islet proliferation. However, the factors regulating menin and the MEN1 gene in the pancreas are poorly understood. Here, we describe the regulation of menin by miR-24 and demonstrate that miR-24 directly decreases menin levels and impacts downstream cell cycle inhibitors in MIN6 insulinoma cells and in ␤lox5 immortalized ␤-cells. This regulation of menin impacts cell viability and proliferation in ␤lox5 cells. Furthermore, our data show a feedback regulation between miR-24 and menin that is present in the pancreas, suggesting that miR-24 regulates menin levels in the pancreatic islet. menin; MEN1; pancreatic islet; miR-24; miRNA THE ENDOCRINE PANCREAS is responsible for maintaining normal glucose homeostasis through the tightly controlled, regulated release of insulin from the pancreatic islet. Pancreatic islets have the unique ability to dynamically and reversibly expand to adapt to changes in insulin demand through careful balance of cell growth and renewal (including ␤-cell replication, neogenesis, transdifferentiation, and hypertrophy), and cell death (apoptosis, atrophy, and autophagy). When this process becomes compromised, it leads to the clinical manifestation of gestational diabetes or type 2 diabetes (T2D). However, detailed knowledge of the mechanisms underlying this process is lacking.MicroRNAs (miRNAs), an evolutionarily conserved class of posttranscriptional regulators, are short ϳ22-nucleotide noncoding RNA sequences that regulate the expression of mRNA targets by binding to the 3=-UTR and inhibiting translation and/or targeting the mRNA for degradation. There is growing evidence that miRNAs regulate key biological processes in the pancreatic islet (13,14,17,27,33,49). For example, miR-375, the first miRNA identified in ␤-cell function, regulates insulin secretion and is essential for normal glucose homeostasis and turnover of ␣-and ␤-cells (40, 41). Other recent studies indicate a role for miR-338-3p and miR-181a in ␤-cell differentiation and insulin sensitivity, respectively (7, 23). p38 (MAPK) is downregulated by miR-24 through the insulinresponsive glucose transporter 4 (GLUT4) to affect peripheral insulin resistance (21). miR-24 also regulates insulin production by targeting the insulin transcriptional repressors Sox6 and Bhlhe22 (35).

Pathobiology of biliary epithelia

“…Moreover, patients with late stage PSC have increased MEN1 expression compared to controls with early disease [102]. MiR-24 can target a complementary site on MEN1, and it has been shown that increasing MEN1 correlates with increasing expression of fibrosis genes (e.g., fibronectin 1, collagen type 1 α 1, tumor growth factor β 1 and α-smooth muscle actin) [102,103]. Menin, the protein product of MEN1, which itself is a tumor suppressor gene, may thus be responsible for mediating the cholangiocyte response cholangiocytes to injury [102].…”

The future: genetics advances in MEN1 therapeutic approaches and management strategies

“…However, a consensus signature of genes affected upon menin loss in MEN1 target tissues warrants further investigation. Regarding the regulation of menin, a microRNA (miR24-1 and its mature form miR24) has been shown to regulate the expression of menin with a feedback mechanism (Luzi, et al 2012; Vijayaraghavan, et al 2014). Further studies of this miRNA that targets menin may shed light on yet another aspect of the multi-functional roles of menin and its regulation.…”

A Review of the Scaffold Protein Menin and its Role in Hepatobiliary Pathology

“…Menin has been shown to directly bind to JunD, an AP-1 transcription factor, to facilitate histone deacetylation and turn off transcription of JunD targets. It has also been shown to enable transcription of mixed-lineage leukemia (MLL) protein target genes by modifying histones with activating tri-methylation marks 9,10 .…”

“…One explanation for menin’s broad and variable role is the 5′ heterogeneity of the MEN1 mRNA transcript 10 . Northern blot, 5′ RACE, and positional deletion studies revealed that the MEN1 transcripts come in two sizes: a ubiquitously expressed 2.8-kb transcript and a larger 4.2-kb transcript with expression restricted to the pancreas and thymus 16 .…”

“…miR-24 binds to the 3′-untranslated region of the MEN1 mRNA transcript to negatively regulate its protein expression. Menin, in turn, can positively regulate expression of miR-24 via MLL-driven histone trimethylation at both of the miR-24 chromosomal locations, chromosomes 9 and 19 10 . Overexpression of menin represses MEN1 promoter activity, indicating negative self-regulation 17 .…”