In search of tumor suppressing functions of menin

Yang, Yuqing; Hua, Xianxin

doi:10.1016/j.mce.2006.12.032

Cited by 89 publications

(69 citation statements)

References 68 publications

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“…The MEN1 gene was successfully identified in 1997, which is composed of ten exons spanning 2.8 kb that codes for a 610 amino acid nuclear protein, known as menin (Chandrasekharappa et al 1997, Lemmens et al 1997. Menin, which has no homology to any other known proteins, is considered to play a role in cell growth regulation, cell cycle, genome stability and synapse plasticity (Yang & Hua 2007). More than 400 germ line and somatic mutations in the MEN1 gene have been identified (http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/ 120173.html).…”

Section: Introductionmentioning

confidence: 99%

MEN1 mutation analysis in Chinese patients with multiple endocrine neoplasia type 1

Jiang

Lu²,

Cui³

et al. 2007

Endocrine Related Cancer

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Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumour syndrome characterized by the development of tumours of the parathyroid, anterior pituitary and pancreatic islets, etc. Heterozygous germ line mutations of MEN1 gene are responsible for the onset of MEN1. We investigated the probands and 31 family members from eight unrelated Chinese families associated with MEN1 and identified four novel mutations, namely 373_374ins18, 822delT, 259delT and 1092delC, as well as three previously reported mutations, such as 357_360delCTGT, 427_428delTA and R108X (CGAOTGA) of MEN1 gene. Furthermore, we detected a loss of heterozygosity (LOH) at chromosome 11q in the removed tumours, including gastrinoma, insulinoma and parathyroid adenoma from two probands of MEN1 families. RT-PCR and direct sequencing showed that mutant MEN1 transcripts remained in the MEN1-associated endocrine tumours, whereas normal menin proteins could not be detected in those tumours by either immunohistochemistry or immunoblotting. In conclusion, MEN1 heterozygous mutations are associated with LOH and menin absence, which are present in MEN1-associated endocrine tumours.

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Section: Introductionmentioning

confidence: 99%

MEN1 mutation analysis in Chinese patients with multiple endocrine neoplasia type 1

Jiang

Lu²,

Cui³

et al. 2007

Endocrine Related Cancer

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“…Among different pathways and factors known to be involved in the control of b-cell proliferation, menin, the protein encoded by the MEN1 gene, is of particular interest. It is not only known as a tumor suppressor in islet cells (Yang and Hua, 2007), but also for its role in adaptive b-cell proliferation (Karnik et al, 2007). Menin is considered as a cofactor of transcriptional regulation, capable of interacting with many transcription factors and other protein partners.…”

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confidence: 99%

“…Menin is considered as a cofactor of transcriptional regulation, capable of interacting with many transcription factors and other protein partners. Although it has been demonstrated that menin inactivation led to acute b-cell proliferation (Schnepp et al, 2006;Yang et al, 2010), several studies of mouse Men1 insulinoma models highlighted the fact that the menin-related tumorigenesis procedure may need the participation of other factors apart from Men1 inactivation (Bertolino et al, 2003b;Crabtree et al, 2003;Loffler et al, 2007;Yang and Hua, 2007).…”

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confidence: 99%

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse

Hamze

Bonnavion

et al. 2011

Oncogene

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MafB, a member of the large Maf transcription factor family, is essential for the embryonic and terminal differentiation of pancreatic a-and b-cells. However, the role of MafB in the control of adult islet-cell proliferation remains unknown. Considering its oncogenic potential in several other tissues, we investigated the possible alteration of its expression in adult mouse b-cells under different conditions of proliferation. We found that MafB, in general silenced in these cells, was reexpressed in B30% of adaptive b-cells both in gestational female mice and in mice fed with a high-fat diet. Importantly, reactivated MafB expression was also observed in the early b-cell lesions and insulinomas that developed in b-cell specific Men1 mutant mice, appearing in >80% of b-cells in hyperplasic or dysplastic islets from the mutant mice >4 months of age. Moreover, MafB expression could be induced by glucose stimulation in INS-1 rat insulinoma cells. The induction was further reinforced following Men1 knockdown by siRNA. Furthermore, MafB overexpression in cultured bTC3 cells enhanced cell foci formation both in culture medium and on soft agar, accompanied with the increased expression of Cyclin B1 and D2. Conversely, MafB downregulation by siRNA transfection reduced BrdU incorporation in INS-1E cells. Taken together, our data reveal that Men1 inactivation leads to MafB reexpression in mouse b-cells in vivo, and provides evidence that deregulated ectopic MafB expression may have a hitherto unknown role in adult b-cell proliferation and Men1-related tumorigenesis.

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“…4 The recently characterized crystal structure of menin demonstrates that it acts as a scaffold protein in regulating gene transcription, cell proliferation, apoptosis and genome stability via its interaction with its various partners. [5][6][7][8] However, MEN-1-affected individuals only develop clinically apparent phenotypic disease in early adulthood because they are protected from tumorigenesis earlier in life by virtue of having one normal tumor-suppressor MEN-1 allele inherited from their unaffected parent. For tumors to develop a second, somatic mutation must occur that inactivates the normal unaffected allele in at risk tissues leading to tumor development.…”

Section: Introductionmentioning

confidence: 99%

PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target

Gurung

Hua

Runske

et al. 2014

Cancer Biology & Therapy

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Pancreatic neuroendocrine tumors (PNETs) are rare, indolent tumors that may occur sporadically or develop in association with well-recognized hereditary syndromes, particularly multiple endocrine neoplasia type 1 (MEN-1). We previously demonstrated that the hedgehog (HH) signaling pathway was aberrantly up-regulated in a mouse model that phenocopies the human MEN-1 syndrome, Men1l/l;RipCre, and that inhibition of this pathway suppresses MEN-1 tumor cell proliferation. We hypothesized that the HH signaling pathway is similarly upregulated in human PNETs. We performed immunohistochemical (IHC) staining for PTCH1 in human fresh and archival PNET specimens to examine whether human sporadic and MEN-1-associated PNETs revealed similar abnormalities as in our mouse model and correlated the results with clinical and demographic factors of the study cohort. PTCH1 staining was positive in 12 of 22 PNET patients (55%). Four of 5 MEN-1 patients stained for PTCH1 (p D 0.32 as compared with sporadic disease patients). Nine of 16 patients with metastatic disease stained for PTCH1 as compared with zero of 3 with localized disease only (p D 0.21). No demographic or clinical features appeared to be predictive of PTCH 1 positivity and PTCH 1 positivity per se was not predictive of clinical outcome. PTCH1, a marker of HH pathway up regulation, is detectable in both primary and metastatic tumors in more than 50% of PNET patients. Although no clinical or demographic factors predict PTCH1 positivity and PTCH1 positivity does not predict clinical outcome, the frequency of expression alone indicates that perturbation of this pathway with agents such as Vismodegib, an inhibitor of Smoothened (SMO), should be examined in future clinical trials.

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In search of tumor suppressing functions of menin

Cited by 89 publications

References 68 publications

MEN1 mutation analysis in Chinese patients with multiple endocrine neoplasia type 1

MEN1 mutation analysis in Chinese patients with multiple endocrine neoplasia type 1

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse

PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target

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