Department of Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America.
PLoS One. 2009 Nov 24;4(11):e8008. doi: 10.1371/journal.pone.0008008.
PERK eIF2alpha kinase is required for the proliferation of the insulin-secreting beta- cells as well as insulin synthesis and secretion. In addition, PERK signaling has been found to be an important factor in determining growth and angiogenesis of specific types of tumors, and was attributed to PERK-dependent regulation of the hypoxic stress response. In this report we examine the role of PERK in regulating proliferation and angiogenesis of transformed beta-cells in the development of insulinomas.
The SV40 Large T-antigen (Tag) was genetically introduced into the insulin secreting beta-cells of Perk KO mice under the control of an inducible promoter. Tumor growth and the related parameters of cell proliferation were measured. In late stage insulinomas the degree of vascularity was determined.
The formation and growth of insulinomas in Perk-deficient mice was dramatically ablated with much fewer tumors, which averaged 38-fold smaller than seen in wild-type control mice. Beta-cell proliferation was ablated in Perk-deficient mice associated with reduced tumor growth. In the small number of large encapsulated insulinomas that developed in Perk-deficient mice, we found a dramatic reduction in tumor vascularity compared to similar sized insulinomas in wild-type mice. Although insulinoma growth in Perk-deficient mice was largely impaired, beta-cell mass was increased sufficiently by T-antigen induction to rescue the hypoinsulinemia and diabetes in these mice.
We conclude that PERK has two roles in the development of beta-cell insulinomas, first to support rapid cell proliferation during the initial transition to islet hyperplasia and later to promote angiogenesis during the progression to late-stage encapsulated tumors.
PERK eIF2alpha 激酶对于胰岛素分泌β细胞的增殖以及胰岛素的合成和分泌都是必需的。此外，PERK 信号已被发现是决定特定类型肿瘤生长和血管生成的重要因素，这归因于 PERK 依赖性调节缺氧应激反应。在本报告中，我们研究了 PERK 在调节转化的β细胞增殖和血管生成在胰岛素瘤发生中的作用。
SV40 大 T 抗原（Tag）在诱导启动子的控制下被遗传引入胰岛素分泌β细胞的 Perk KO 小鼠中。肿瘤生长和细胞增殖的相关参数被测量。在晚期胰岛素瘤中，测定血管密度。
Perk 缺陷型小鼠的胰岛素瘤形成和生长明显被抑制，肿瘤数量明显减少，平均体积比野生型对照组小鼠小 38 倍。Perk 缺陷型小鼠的β细胞增殖被抑制与肿瘤生长减少相关。在 Perk 缺陷型小鼠中形成的少数大包裹性胰岛素瘤中，与野生型小鼠中相似大小的胰岛素瘤相比，肿瘤血管密度显著降低。尽管 Perk 缺陷型小鼠的胰岛素瘤生长受到很大的损害，但 T 抗原诱导使β细胞质量增加足以挽救这些小鼠的低胰岛素血症和糖尿病。
我们得出结论，PERK 在β细胞胰岛素瘤的发生发展中具有两个作用，首先是在向胰岛增生的初始过渡期间支持快速细胞增殖，其次是在向晚期包裹性肿瘤进展期间促进血管生成。
