Foxa2, a novel protein partner of the tumour suppressor menin, is deregulated in mouse and human MEN1 glucagonomas
Foxa2, a novel protein partner of the tumour suppressor menin, is deregulated in mouse and human MEN1 glucagonomas
复制标题
Foxa2 是肿瘤抑制蛋白 menin 的新型蛋白伴侣，在小鼠和人类 MEN1 胰高血糖素瘤中失调
DOI：
10.1002/path.4885
复制
发表时间：
2017-05-01
影响因子：
7.3
通讯作者：
Zhang, Chang Xian
中科院分区：
文献类型：
--
作者：
Bonnavion, Remy;Teinturier, Romain;Zhang, Chang Xian
Foxa 2是胰岛的先驱因子之一，在胰岛发育和内分泌功能中起着至关重要的作用。其表达和生物学功能受多种因素调节，特别是包括胰岛素和胰高血糖素。然而，其在成人胰腺α细胞中的表达和生物学作用仍然难以捉摸。在目前的研究中，我们发现Foxa 2在α细胞特异性Men 1突变小鼠的胰岛中过表达，无论是在转录水平还是在蛋白水平。更重要的是，免疫染色分析显示，在Men 1破坏后的非常早期阶段，其显著的核积累，特别是在α细胞中。在相当大比例（12/19）的人多发性内分泌瘤1型（MEN 1）胰高血糖素瘤中也检测到类似的细胞核FOXA 2表达。有趣的是，我们的数据揭示了Foxa 2和Men 1基因编码的menin之间的相互作用。此外，使用几种方法，我们证明了这种相互作用在两个测试的Foxa 2靶基因的调节，包括Foxa 2自身的Foxa 2启动子的自动调节的相关性。目前的研究建立了menin，Foxa 2的一种新的蛋白质伴侣，作为Foxa 2的调节剂，其生物学功能超出了胰腺内分泌细胞。版权所有© 2017大不列颠及爱尔兰病理学会。由John Wiley & Sons有限公司出版
Foxa2, known as one of the pioneer factors, plays a crucial role in islet development and endocrine functions. Its expression and biological functions are regulated by various factors, including, in particular, insulin and glucagon. However, its expression and biological role in adult pancreatic α‐cells remain elusive. In the current study, we showed that Foxa2 was overexpressed in islets from α‐cell‐specific Men1 mutant mice, at both the transcriptional level and the protein level. More importantly, immunostaining analyses showed its prominent nuclear accumulation, specifically in α‐cells, at a very early stage after Men1 disruption. Similar nuclear FOXA2 expression was also detected in a substantial proportion (12/19) of human multiple endocrine neoplasia type 1 (MEN1) glucagonomas. Interestingly, our data revealed an interaction between Foxa2 and menin encoded by the Men1 gene. Furthermore, using several approaches, we demonstrated the relevance of this interaction in the regulation of two tested Foxa2 target genes, including the autoregulation of the Foxa2 promoter by Foxa2 itself. The current study establishes menin, a novel protein partner of Foxa2, as a regulator of Foxa2, the biological functions of which extend beyond the pancreatic endocrine cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.