Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the
            <i>Men1</i>
            gene

Yang, Yuqing; Gurung, Buddha; Wu, Ting; Wang, Haoren; Stoffers, Doris A.; Hua, Xianxin

doi:10.1073/pnas.1012257107

Cited by 45 publications

(66 citation statements)

References 34 publications

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“…As menin was previously reported to be downregulated during adaptive b-cell proliferation (Karnik et al, 2007), we also examined menin expression and its potential correlation with MafB reexpression in pregnant (Supplementary Figure S4) or high-fat-fed mice (data not shown). No decrease in menin expression was evident in both conditions, consistent with a recent report where menin expression levels in islets were found unchanged in mice fed with a high-fat diet (Yang et al, 2010), thus no correlation could be found between ectopic MafB expression and menin expression levels.…”

supporting

confidence: 91%

“…Furthermore, as shown in Figure 4a, we observed that MAFBoverexpressing bTC3-cells displayed the upregulated expression of both Cyclin D2, a previously identified MafB target gene in myeloma cells (van Stralen et al, 2009), and Cyclin B1 (Figure 4a). Factors in both Cyclin D and Cyclin B families were previously reported to be upregulated in mouse Men1 insulinomas (Fontaniere et al, 2006) and in mouse b-cells, with acute Men1-ablation (Yang et al, 2010). To confirm the above results, MafB was knocked-down by siRNA transfec- þ / þ -RipCre þ and three Men1 F/F -RipCre À mice, respectively) by real-time RT-PCR was carried out as previously described (Fontaniere et al, 2006).…”

mentioning

confidence: 61%

“…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).…”

mentioning

confidence: 99%

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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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confidence: 91%

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confidence: 61%

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confidence: 99%

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

Hamze

Bonnavion

et al. 2011

Oncogene

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“…They were then crossed with Ubc9 promoter driven Cre-ER mice (C57B6 background) as previously described (19). Men1 f/f and Men1 f/f ;Cre-ER mice were as described previously (20). Animal genotyping was done by PCR according to published methods using DNA extracted from tails.…”

Section: Methodsmentioning

confidence: 99%

Interplay between Menin and K-Ras in Regulating Lung Adenocarcinoma

Feng

Gao

et al. 2012

Journal of Biological Chemistry

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Background:The role of MEN1 gene in development of lung cancer is poorly understood. Results: K-Ras inhibits menin expression via increasing DNA methylation, whereas menin inhibits Ras-mediated signaling via suppressing activation of Ras. Conclusion:The interplay between K-Ras and menin plays an important role in regulating the development of lung cancer. Significance: These results have unraveled a novel mechanism underlying menin-mediated repression of lung cancer.

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“…We next speculated that an autocrine factor produced by tumor cells promotes the loss of insulin expression. We explored transcriptomic analyses of Men1-KO ␤-cell and insulinoma models (29,30), looking for candidates known to inhibit insulin expression. Given the importance of TGF-␤ signaling in insulin synthesis and maintenance of ␤-cell maturity (24, 31), we paid particular attention to related ligands.…”

Section: Resultsmentioning

confidence: 99%

ActivinB Is Induced in Insulinoma To Promote Tumor Plasticity through a β-Cell-Induced Dedifferentiation

Ripoche

Charbord

Hennino

et al. 2016

Molecular and Cellular Biology

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cLoss of pancreatic ␤-cell maturity occurs in diabetes and insulinomas. Although both physiological and pathological stresses are known to promote ␤-cell dedifferentiation, little is known about the molecules involved in this process. Here we demonstrate that activinB, a transforming growth factor ␤ (TGF-␤)-related ligand, is upregulated during tumorigenesis and drives the loss of insulin expression and ␤-cell maturity in a mouse insulinoma model. Our data further identify Pax4 as a previously unknown activinB target and potent contributor to the observed ␤-cell dedifferentiation. More importantly, using compound mutant mice, we found that deleting activinB expression abolishes tumor ␤-cell dedifferentiation and, surprisingly, increases survival without significantly affecting tumor growth. Hence, this work reveals an unexpected role for activinB in the loss of ␤-cell maturity, islet plasticity, and progression of insulinoma through its participation in ␤-cell dedifferentiation. Loss of maturity and acquisition of embryonic traits are wellestablished paradigms that contribute to tumor heterogeneity and metastasis (1, 2). Endocrine tumors that develop from pancreatic islet cells are highly heterogeneous (3). Although poorly differentiated endocrine tumors of the pancreas exist, the cause and contribution of ␤-cell dedifferentiation in the initiation and progression of those lesions remain undetermined. Loss of insulin expression has been observed in transgenic mouse models of insulinoma, supporting the existence of a mechanism that reverts the differentiated state of mature ␤ cells in ␤-cell tumors (4, 5). Recently, Landsman et al. demonstrated that elevated Hedgehog/ Gli signaling in ␤ cells alters their identity and leads to the development of undifferentiated endocrine pancreatic tumors (6). Therefore, the participation of ␤-cell dedifferentiation in adult pancreatic pathologies such as islet tumors underscores the need to identify the autocrine factors controlling these mechanisms.While the characterization of signals that regulate ␤-cell development and regeneration is the focus of intense work (7), less is known about mechanisms and molecules that control the differentiation state of mature adult ␤ cells under pathological conditions. The phenomenon of ␤-cell dedifferentiation, characterized by a loss of expression of key ␤-cell genes, such as those encoding insulin, glucose transporter 2 (Glut2), and transcription factors associated with the cells' mature phenotype, was first reported in mouse and recently confirmed in cultured human islets in the absence of any pathological context (8-10). Further evidence has confirmed that the differentiated state of mature adult ␤ cells is not permanent and is lost in response to signals such as oxidative stress and changes in transcriptional profile (11-13). The contribution of ␤-cell dedifferentiation to pathological conditions in vivo is also supported by recent work suggesting that ␤-cell dedifferentiation caused by FoxO1 disruption underlies ␤-cell failure in type...

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Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene

Cited by 45 publications

References 34 publications

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

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

Interplay between Menin and K-Ras in Regulating Lung Adenocarcinoma

ActivinB Is Induced in Insulinoma To Promote Tumor Plasticity through a β-Cell-Induced Dedifferentiation

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