Nuclear-Cytoplasmic Shuttling of Menin Regulates Nuclear Translocation of β-Catenin

Cao, Yanan; Liu, Ruixin; Jiang, Xin; Lu, Jieli; Jiang, Jingjing; Zhang, Chang Xian; Li, Xiaoying; Ning, Guang

doi:10.1128/mcb.00335-09

Cited by 94 publications

(80 citation statements)

References 45 publications

(72 reference statements)

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“…At partial support to our hypothesis concerning a localization defect of menin in PETs, there is a recent paper by Cao et al (2009), which demonstrated in vitro that menin is able to shuttle between nucleus and cytoplasm through newly identified nuclear export signals (NES). More interestingly, menin was shown to directly interact with b-catenin and, when overexpressed, to prevent the nuclear accumulation of b-catenin carrying the protein outside the nucleus.…”

Section: Discussionsupporting

confidence: 65%

MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases

Corbo¹,

Dalai²,

Scardoni³

et al. 2010

Endocrine-Related Cancer

140

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Pancreatic endocrine tumors (PETs) may be part of hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. While MEN1 gene mutation is the only ascertained genetic anomaly described in PETs, no data exist on the cellular localization of MEN1-encoded protein, menin, in normal pancreas and PETs. A total of 169 PETs were used to assess the i) MEN1 gene mutational status in 100 clinically sporadic PETs by direct DNA sequencing, ii) immunohistochemical expression of menin in normal pancreas and 140 PETs, including 71 cases screened for gene mutations, and iii) correlation of these findings with clinical-pathological parameters. Twentyseven PETs showed mutations that were somatic in 25 patients and revealed to be germline in 2 patients. Menin immunostaining showed strong nuclear and very faint cytoplasmic signal in normal islet cells, whereas it displayed abnormal location and expression levels in 80% of tumors. PETs harboring MEN1 truncating mutations lacked nuclear protein, and most PETs with MEN1 missense mutations showed a strong cytoplasmic positivity for menin. Menin was also misplaced in a significant number of cases lacking MEN1 mutations. In conclusion, the vast majority of PETs showed qualitative and/or quantitative alterations in menin localization. In 30% of cases, this was associated with MEN1 mutations affecting sequences involved in nuclear localization or protein-protein interaction. In cases lacking MEN1 mutations, the alteration of one of the menin interactors may have prevented its proper localization, as suggested by recent data showing that menin protein shuttles between the nucleus and cytoplasm and also affects the subcellular localization of its interactors.

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Section: Discussionsupporting

confidence: 65%

MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases

Corbo¹,

Dalai²,

Scardoni³

et al. 2010

Endocrine-Related Cancer

140

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“…It has an essential role in Wnt/ b-catenin signaling through histone methylation of downstream target gene promoters . Menin is also able to directly interact with b-catenin and carry b-catenin out of the nucleus (Cao et al 2009). These results imply that menin may regulate the production of neuropathic pain through interacting with Wnt/b-catenin signaling.…”

Section: Discussionmentioning

confidence: 99%

Early Changes of β-Catenins and Menins in Spinal Cord Dorsal Horn after Peripheral Nerve Injury

et al. 2010

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Injury to the peripheral nervous system can lead to spontaneous pain, hyperalgesia and allodynia. Previous studies have shown sprouting of Abeta-fibres into lamina II of the spinal cord dorsal horn after nerve injury and the formation of new synapses by these sprouts. beta-Catenin and menin as synaptogenic factors are critically involved in synapse formation. However, the roles of beta-catenin and menin in neuropathic pain are still unclear. Using Western blot analysis we investigated the changes of beta-catenin and menin in the spinal dorsal horn after unilateral spared nerve injury (SNI). We demonstrated an increase in both beta-catenin and menin protein levels in the ipsilateral spinal dorsal horn at days 1 and 3 following spared nerve injury (P < 0.05). These increases were associated with changes in paw withdrawal threshold to mechanical stimuli and weight bearing deficit suggestive of pain behavior and spontaneous ongoing pain respectively. However, the injury-associated increases in beta-catenins and menins levels returned to control levels at day 14. In conclusion, these results indicate that peripheral nerve injury induces upregulation of beta-catenins and menins in the dorsal horn of the spinal cord, which may contribute to the development of chronic neuropathic pain. Antagonists of these molecules may serve as new therapeutic agents.

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“…Three distinct types (MEN-1, MEN-2A, MEN-4) are associated with HPT 32 42 141 143 . MEN-1 syndrome is caused by germline inactivating mutations in the tumour suppressor gene MEN1 (11q13), encoding ‘menin’ protein, which is thought to prevent nuclear translocation of β-catenin, thereby suppressing Wnt/β-catenin signalling, a well-known tumorigenesis pathway 32 42 141 143 175. Phenotypically, MEN-1 is characterised by the development of multiglandular parathyroid adenomas (90%), gastroenteropancreatic neuroendocrine tumours (60%) and pituitary adenomas (30%); additional tumours reported in this syndrome include adrenocortical tumours, facial angiofibromas, collagenomas, lipomas and/or other neuroendocrine tumours of various sites (thymus, lung, stomach) 32 42 85 99 141 143 176.…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

Clinicopathological correlates of hyperparathyroidism

2015

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Hyperparathyroidism is a common endocrine disorder with potential complications on the skeletal, renal, neurocognitive and cardiovascular systems. While most cases (95%) occur sporadically, about 5% are associated with a hereditary syndrome: multiple endocrine neoplasia syndromes (MEN-1, MEN-2A, MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH-1, FHH-2, FHH-3), familial hypercalciuric hypercalcaemia, neonatal severe hyperparathyroidism and isolated familial hyperparathyroidism. Recently, molecular mechanisms underlying possible tumour suppressor genes (MEN1, CDC73/HRPT2, CDKIs, APC, SFRPs, GSK3β, RASSF1A, HIC1, RIZ1, WT1, CaSR, GNA11, AP2S1) and proto-oncogenes (CCND1/PRAD1, RET, ZFX, CTNNB1, EZH2) have been uncovered in the pathogenesis of hyperparathyroidism. While bi-allelic inactivation of CDC73/HRPT2 seems unique to parathyroid malignancy, aberrant activation of cyclin D1 and Wnt/β-catenin signalling has been reported in benign and malignant parathyroid tumours. Clinicopathological correlates of primary hyperparathyroidism include parathyroid adenoma (80–85%), hyperplasia (10–15%) and carcinoma (<1–5%). Secondary hyperparathyroidism generally presents with diffuse parathyroid hyperplasia, whereas tertiary hyperparathyroidism reflects the emergence of autonomous parathyroid hormone (PTH)-producing neoplasm(s) from secondary parathyroid hyperplasia. Surgical resection of abnormal parathyroid tissue remains the only curative treatment in primary hyperparathyroidism, and parathyroidectomy specimens are frequently encountered in this setting. Clinical and biochemical features, including intraoperative PTH levels, number, weight and size of the affected parathyroid gland(s), are crucial parameters to consider when rendering an accurate diagnosis of parathyroid proliferations. This review provides an update on the expanding knowledge of hyperparathyroidism and highlights the clinicopathological correlations of this prevalent disease.

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Nuclear-Cytoplasmic Shuttling of Menin Regulates Nuclear Translocation of β-Catenin

Cited by 94 publications

References 45 publications

MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases

MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases

Early Changes of β-Catenins and Menins in Spinal Cord Dorsal Horn after Peripheral Nerve Injury

Clinicopathological correlates of hyperparathyroidism

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