Direct interaction of menin leads to ubiquitin-proteasomal degradation of β-catenin

Kim, Byungho; Song, Tae-Yang; Jung, Kwan Young; Kim, Seul Gi; Cho, Eun Jung

doi:10.1016/j.bbrc.2017.08.011

Cited by 12 publications

(12 citation statements)

References 24 publications

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“…It was reported that miR-340 was down-regulated in EOC and exerted anti-tumor effects by targeting four and a half LIM domain protein 2 (FHL2), a co-activator of β-catenin [106]. Another study reported that miR-762 promoted EOC cell proliferation, migration, and invasion by upregulating Wnt/β-catenin signalling via suppression of menin [101], which has been reported to promote β-catenin cytoplasmic shuttling and degradation [129, 130]. Finally, miR-377, miR-101, miR-381, and miR-429 were found to target Cullin E3-Ring E3-ligase family member, CUL4A, membrane-associated E3 ubiquitin ligase MARCH7, transcription factor Ying Yang 1 (YY1), and the PNCA-associated factor, KIAA0101, respectively, in EOC [108, 114, 115, 117].…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis

et al. 2019

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Epithelial ovarian cancer (EOC) is the deadliest female malignancy. The Wnt/β-catenin pathway plays critical roles in regulating embryonic development and physiological processes. This pathway is tightly regulated to ensure its proper activity. In the absence of Wnt ligands, β-catenin is degraded by a destruction complex. When the pathway is stimulated by a Wnt ligand, β-catenin dissociates from the destruction complex and translocates into the nucleus where it interacts with TCF/LEF transcription factors to regulate target gene expression. Aberrant activation of this pathway, which leads to the hyperactivity of β-catenin, has been reported in ovarian cancer. Specifically, mutations of CTNNB1, AXIN, or APC, have been observed in the endometrioid and mucinous subtypes of EOC. In addition, upregulation of the ligands, abnormal activation of the receptors or intracellular mediators, disruption of the βcatenin destruction complex, inhibition of the association of β-catenin/E-cadherin on the cell membrane, and aberrant promotion of the β-catenin/TCF transcriptional activity, have all been reported in EOC, especially in the high grade serous subtype. Furthermore, several non-coding RNAs have been shown to regulate EOC development, in part, through the modulation of Wnt/β-catenin signalling. The Wnt/β-catenin pathway has been reported to promote cancer stem cell self-renewal, metastasis, and chemoresistance in all subtypes of EOC. Emerging evidence also suggests that the pathway induces ovarian tumor angiogenesis and immune evasion. Taken together, these studies demonstrate that the Wnt/β-catenin pathway plays critical roles in EOC development and is a strong candidate for the development of targeted therapies.

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Section: Introductionmentioning

confidence: 99%

Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis

et al. 2019

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“…Они продемонстрировали, что мутации в доменах, ответствен-ных за ядерные экспортные сигналы, могут нарушать экспортную функцию менина. Эти и результаты других исследований предполагают, что патологические состояния, затрагивающие функции менина, могут изменять клеточную локализацию его интерактора (например, β-катенина) и позволяют сделать предположение о том, что аномальная экспрессия менина может возникнуть в случае каких-либо изменений со стороны его интерактора (например, опухоли могут накапливать другие мутации, которые способны изменять экспрессию интерактора) [22][23][24].…”

Section: Discussionunclassified

Morphological characteristics of pituitary adenomas in the phenocopy of multiple endocrine neoplasia type 1

Trukhina

Mamedova

Лапшина

et al. 2021

Probl Endokrinol (Mosk)

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BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is a rare autosomal dominant disorder caused by mutations in the MEN1 gene, which encodes the menin protein. If a patient has the MEN 1 phenotype in the absence of mutations in the MEN1 gene, the condition is classified as a phenocopy of this syndrome. Although significant progress has been made in understanding the function of menin, its role in the oncogenesis of the endocrine glands is still being elucidated. Due to its key role in physiological and pathological processes, the assessment of the menin expression can provide valuable information.AIM: to determine whether there are any differences in the expression of menin in the pituitary adenomas (PA) in patients with phenocopy of MEN 1 (phMEN 1) and genetically confirmed MEN 1 (gMEN 1) compared with their sporadic forms.MATERIALS AND METHODS: immunohistochemical assessment of the menin expression was carried out in PA of patients with gMEN 1, phMEN 1 and sporadic acromegaly (SA), surgically treated in 2008–2020. IHC was performed using antibodies to menin, PRL, GH, ACTH, FSH, TSH, Pit-1, T-box, ERA on previously prepared histological section.RESULTS: The study included 35 samples of PA: gMEN 1 — 9 samples, phMEN 1 — 12 (somatotropinomas + PHPT); CA — 14 samples. The patients were comparable by gender, adenoma size, and drug intake. The gMEN 1 group differed from phMEN 1 and SA by age (p = 0.0005). In patients with gMEN 1, the expression of menin varied from no staining (5/9) to intense cytoplasm staining. Cytoplasmic expression of menin was mainly present (11/12) in the phMEN 1. In the SA group, there was no staining in 1 case; nuclear expression was detected in 6/14 cases. The phMEN 1 group showed significantly higher cytoplasmic expression of menin than the gMEN 1 group (p = 0.006). The gMEN 1 group also differed from the SA group (p = 0.012). There were no statistically significant differences between the phMEN 1 and SA groups (p = 0.049).CONCLUSION: It was revealed that the menin expression, in general, is retained in phMEN 1 and SA groups, although with different localization in the cell structure (nucleus and / or cytoplasm). At the same time, the expression of menin varies greatly in patients with gMEN 1. According to the data obtained, it can be assumed that the pathogenesis of PA in phMEN 1 and SA may have similarities; however, there could be factors contributing to the appearance of several tumors of the endocrine glands in one person with phMEN 1. To understand this process, it is necessary to further study the genes associated with MEN 1, epigenetic factors, signaling pathways in which menin is involved.

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“…In silico functional analysis revealed variants in genes associated with tumourigenic pathways, including Kras, Wnt2b, Il3ra and Tnfrsf10a, which were associated with Kras, wnt, interleukin and apoptosis signalling, respectively. These genes have potential to be MEN1 modifiers, as the Men1 protein product, menin, has been shown to: repress MAPK-driven proliferation downstream of KRAS (28), control wnt signalling through interaction with β-catenin (36,37,38), regulate expression of interleukins (39) and promote TNF-α induced apoptosis through up-regulation of caspase 8 (40). In addition, an association between a cyclin dependent kinase inhibitor 1B (Cdkn1b) variant (c.326T>G) and tumour multiplicity in MEN1 patients has been reported (41), although we did not observe any variants in Cdkn1b (encoding p27 kip1 ) in our WGS data, we did observe variants in the cell cycle regulator, Ccne2, that is regulated by p27 kip1 .…”

Section: Discussionmentioning

confidence: 99%

Genetic background influences tumour development in heterozygous Men1 knockout mice

Lines

Javid

Reed

et al. 2020

Endocrine Connections

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Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1.

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Direct interaction of menin leads to ubiquitin-proteasomal degradation of β-catenin

Cited by 12 publications

References 24 publications

Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis

Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis

Morphological characteristics of pituitary adenomas in the phenocopy of multiple endocrine neoplasia type 1

Genetic background influences tumour development in heterozygous Men1 knockout mice

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