Menin-mediated Caspase 8 Expression in Suppressing Multiple Endocrine Neoplasia Type 1

Department of Developmental Biology , Stanford University, Palo Alto, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2007; 282(43):31332-40. DOI: 10.1074/jbc.M609555200
Source: PubMed


Multiple endocrine neoplasia type 1 (MEN1) is a familial tumor syndrome linked to mutation of the MEN1 gene, which encodes a tumor suppressor, menin. We previously reported that menin up-regulates the caspase 8 expression and promotes TNF-alpha-induced apoptosis. However, it remains unclear how menin up-regulates caspase 8 expression and whether menin-mediated caspase 8 expression plays a role in repressing MEN1 development. Here we show that menin binds the 5'-untranslated region (5'-UTR) of the Caspase 8 locus in vivo and activates transcription of a reporter gene through the 5'-UTR. Menin directly binds the 5'-UTR in a sequence-independent manner in vitro. Moreover, Men1 ablation in cells reduces acetylation of histones H3 and H4 at the 5'-UTR of the caspase 8 locus bound by menin in vivo. Notably, the MEN1-derived menin point mutants lose their ability to bind the caspase 8 locus and fail to induce caspase 8 expression and TNF-alpha-mediated apoptosis. Consistent with these observations, the expression level of caspase 8 is markedly reduced in insulinomas from Men1(+/-) mice. Together, our results indicate that menin enhances the caspase 8 expression by binding the caspase 8 locus, and suggest that menin suppresses MEN1 tumorigenesis, at least in part, by up-regulating caspase 8 expression.

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    • "Recent data suggest that interactions between menin and menin-interacting proteins have a role in physiological regulation of embryological development [38], cell differentiation [39], cell proliferation [40], apoptosis [41], DNA-damage repair [34] [35], and endocrine/metabolic functions [42]. The role of menin in regulating cellular proliferation is one of its best-studied functions . "
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    ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) results from mutations in the tumor suppressor gene, MEN1, which encodes nuclear protein menin. Menin is important for suppressing tumorigenesis in various endocrine and certain non-endocrine tissues. Although menin suppresses MEN1 through a variety of mechanisms including regulating apoptosis and DNA repair, the role of menin in regulating cell proliferation is one of the best-studied functions. Here, we focus on reviewing various mechanisms underlying menin-mediated inhibition of cell proliferation. Menin inhibits cell proliferation to repress MEN1 through multiple mechanisms. 1) Menin interacts with various histonemodifying enzymes, such as MLL, EZH2 and HDACs, to affect gene transcription, leading to repression of cell proliferation. 2) Menin also interacts with various transcription factors, such as JunD, NF-κB, PPARγ and VDR, to induce or suppress gene transcription. As these various transcription factors are known to regulate cell proliferation, their interaction with menin may be relevant to menin's role in inhibiting cell proliferation. 3) Menin inhibits cell proliferation via TGF-β signaling and Wnt/β-catenin signaling pathways. 4) Menin represses certain pro-proliferative factors involved in endocrine tumors such as IGFBP-2, IGF2 and PTHrP to repress cell proliferation. 5) Menin affects cell cycle progression to inhibit cell proliferation. This review is helpful in our understanding of the comprehensive mechanisms whereby menin represses MEN1 through inhibiting cell proliferation.
    American Journal of Cancer Research 01/2011; 1(6):726-39. · 4.17 Impact Factor
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    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.
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    ABSTRACT: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by the occurrence of tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene, consists of 10 exons that encode a 610-amino acid protein referred to as Menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division and proliferation. Germ-line mutations usually result in MEN1 or occasionally in an allelic variant referred to as Familial Isolated Hyperparathyroidism (FIHP). MEN1 tumours frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumour suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumours. To date, over 1300 mutations have been reported, and the majority (>70%) of these are predicted to lead to truncated forms of Menin. The mutations are scattered throughout the >9 kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83–84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210–211) have been reported to occur frequently in 4.5%, 2.7%, 2.6% and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype–genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of Menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation.
    European Journal of Cancer 02/1994; 30A(13):1961-8. DOI:10.1016/j.beem.2010.07.003 · 5.42 Impact Factor
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