The Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Mol Cell Biol. 2012 Dec;32(24):5129-39. doi: 10.1128/MCB.01009-12. Epub 2012 Oct 15.
Germ line PERK mutations are associated with diabetes mellitus and growth retardation in both rodents and humans. In contrast, late embryonic excision of PERK permits islet development and was found to prevent onset of diabetes, suggesting that PERK may be dispensable in the adult pancreas. To definitively establish the functional role of PERK in adult pancreata, we generated mice harboring a conditional PERK allele in which excision is regulated by tamoxifen administration. Deletion of PERK in either young adult or mature adult mice resulted in hyperglycemia associated with loss of islet and β cell architecture. PERK excision triggered intracellular accumulation of proinsulin and Glut2, massive endoplasmic reticulum (ER) expansion, and compensatory activation of the remaining unfolded-protein response (UPR) signaling pathways specifically in pancreatic tissue. Although PERK excision increased β cell death, this was not a result of decreased proliferation as previously reported. In contrast, a significant and specific increase in β cell proliferation was observed, a result reflecting increased cyclin D1 accumulation. This work demonstrates that contrary to expectations, PERK is required for secretory homeostasis and β cell survival in adult mice.
种系 PERK 突变与啮齿动物和人类的糖尿病和生长迟缓有关。相比之下，PERK 的晚期胚胎缺失允许胰岛发育，并被发现可预防糖尿病的发生，这表明 PERK 在成年胰腺中可能不是必需的。为了明确确定 PERK 在成年胰腺中的功能作用，我们生成了一种条件性 PERK 等位基因的小鼠，其缺失可通过他莫昔芬给药来调节。在年轻成年或成熟成年小鼠中删除 PERK 会导致高血糖，伴有胰岛和β细胞结构的丧失。PERK 缺失会触发胰岛素原和 Glut2 的细胞内积累、内质网（ER）的大量扩张，以及剩余未折叠蛋白反应（UPR）信号通路的代偿性激活，这在胰腺组织中是特异性的。尽管 PERK 缺失增加了β细胞死亡，但这并不是先前报道的增殖减少的结果。相反，观察到β细胞增殖显著且特异性增加，这是由于 cyclin D1 积累增加的结果。这项工作表明，与预期相反，PERK 是成年小鼠分泌稳态和β细胞存活所必需的。
