Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Biochem Biophys Res Commun. 2020 Aug 27;529(3):826-833. doi: 10.1016/j.bbrc.2020.05.155. Epub 2020 Jul 17.
Maturity-onset diabetes of the young type 3 (MODY3) is caused by mutations in a gene encoding transcription factor hepatocyte nuclear factor 1-alpha (HNF1A). Although the roles of HNF1A in regulation of hepatic and pancreatic genes to maintain glucose homeostasis were investigated, the functions of HNF1A are not completely elucidated. To better understand the functions of HNF1A, we characterized mutations of HNF1A in Thai MODY3 patients and studied the functions of wild-type HNF1A and variant proteins. We demonstrate for the first time that HNF1A upregulates transactivation of an anti-apoptotic gene BCL2 Like 1 (BCL2L1) and that all the identified HNF1A variants including p.D80V, p.R203C, p.P475L, and p.G554fsX556, reduce this ability. The four HNF1A variants impair HNF1A function in promoting INS-1 cell transition from G1 to S phase of cell cycle, which thereby retard cell growth. This finding indicates the role of HNF1A in beta-cell viability by upregulation of anti-apoptotic gene expression and also reaffirms its role in beta-cell growth through cell cycle control.
青年发病型糖尿病 3 型（MODY3）是由编码转录因子肝细胞核因子 1-α（HNF1A）的基因突变引起的。尽管已经研究了 HNF1A 在调节肝和胰腺基因以维持葡萄糖内稳态中的作用，但 HNF1A 的功能尚未完全阐明。为了更好地了解 HNF1A 的功能，我们对泰国 MODY3 患者的 HNF1A 突变进行了特征描述，并研究了野生型 HNF1A 和变异蛋白的功能。我们首次证明 HNF1A 上调抗凋亡基因 BCL2 样 1（BCL2L1）的反式激活，并且所有鉴定的 HNF1A 变体，包括 p.D80V、p.R203C、p.P475L 和 p.G554fsX556，均降低了这种能力。这四种 HNF1A 变体通过抑制 INS-1 细胞从细胞周期的 G1 期向 S 期的转变，从而阻碍细胞生长，损害 HNF1A 促进功能。这一发现表明 HNF1A 通过上调抗凋亡基因表达在β细胞存活中起作用，并通过细胞周期控制再次证实其在β细胞生长中的作用。
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