Mutations in the gene encoding hepatocyte nuclear factor (HNF)1beta result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing beta-cell mass. The functional role of HNF1beta in normal beta-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1beta, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic beta-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1beta was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1beta also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent beta-cells are sensitive to increased expression of WT HNF1beta and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.

译文

:编码肝细胞核因子(HNF)1beta的基因突变会削弱胰岛素分泌反应,并可能减少β细胞的数量,从而导致年轻的(MODY)5发病。 HNF1beta在正常的β细胞中的功能作用了解甚少。因此,在本研究中,野生型(WT)HNF1beta或两个自然发生的MODY5突变之一(激活突变P328L329del或显性负性形式A263insGG)在胰腺β细胞系中有条件表达,胰岛素-1(INS-1),并检查其功能后果。出人意料的是,显性负突变体的过表达并未改变所研究细胞的任何功能特性(包括胰岛素分泌,细胞生长和生存力)。相比之下,WT HNF1beta的表达与INS-1细胞增殖的时间和剂量依赖性抑制以及凋亡的显着增加有关。 WT HNF1beta的诱导还抑制了胰岛素对营养刺激,膜去极化或蛋白激酶A和C活化的分泌反应,这与胰十二指肠同源盒1蛋白水平的显着降低有关。然而,由于P328L329del突变体的表达导致细胞增殖率降低,但是胰岛素分泌的减弱与增殖抑制和生存力丧失分离,但不能诱导细胞凋亡或改变胰岛素分泌。综上所述,本发明结果表明成熟的啮齿动物β细胞对WTHNF1β表达的增加敏感,并且暗示该蛋白的水平被严格调节以维持分泌能力和细胞生存力。

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