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
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DOI：
10.1038/onc.2011.538
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发表时间：
2012-08-01
期刊：
影响因子：
8
通讯作者：
Zhang, C. X.
中科院分区：
文献类型：
--
作者：
Lu, J.;Hamze, Z.;Zhang, C. X.
MafB 是 Maf 大转录因子家族的成员，对于胰腺 α 和 β 细胞的胚胎和终末分化至关重要。然而，MafB 在控制成体胰岛细胞增殖中的作用仍不清楚。考虑到其在其他几种组织中的致癌潜力，我们研究了其在不同增殖条件下成年小鼠β细胞中表达的可能变化。我们发现，MafB 在这些细胞中总体上被沉默，但在妊娠雌性小鼠和高脂肪饮食喂养的小鼠中，大约 30% 的适应性 β 细胞中重新表达。重要的是，在β细胞特异性Men1突变小鼠的早期β细胞病变和胰岛素瘤中也观察到了重新激活的MafB表达，出现在> 4月龄突变小鼠的增生或发育不良胰岛中> 80％的β细胞中。此外，INS-1 大鼠胰岛素瘤细胞中葡萄糖刺激可诱导 MafB 表达。通过 siRNA 敲除 Men1 后，诱导作用进一步增强。此外，培养的 β TC3 细胞中 MafB 的过表达增强了培养基和软琼脂上细胞灶的形成，同时 Cyclin B1 和 D2 的表达增加。相反，通过 siRNA 转染下调 MafB 会减少 INS-1E 细胞中 BrdU 的掺入。综上所述，我们的数据表明，Men1 失活导致小鼠体内 β 细胞中 MafB 重新表达，并提供证据表明，异位 MafB 表达失调可能在成人 β 细胞增殖和 Men1 相关肿瘤发生中发挥迄今为止未知的作用。癌基因 (2012) 31, 3647-3654; doi：10.1038/onc.2011.538； 2011 年 11 月 28 日在线发布
MafB, a member of the large Maf transcription factor family, is essential for the embryonic and terminal differentiation of pancreatic alpha- and beta-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 beta-cells under different conditions of proliferation. We found that MafB, in general silenced in these cells, was reexpressed in similar to 30% of adaptive beta-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 beta-cell lesions and insulinomas that developed in beta-cell specific Men1 mutant mice, appearing in >80% of beta-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 beta TC3 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 beta-cells in vivo, and provides evidence that deregulated ectopic MafB expression may have a hitherto unknown role in adult beta-cell proliferation and Men1-related tumorigenesis. Oncogene (2012) 31, 3647-3654; doi:10.1038/onc.2011.538; published online 28 November 2011