PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice.
PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice.
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DOI：
10.1371/journal.pone.0008008
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发表时间：
2009-11-24
期刊：
影响因子：
3.7
通讯作者：
Cavener DR
中科院分区：
文献类型：
--
作者：
Gupta S;McGrath B;Cavener DR
PERK eIF2 α激酶是胰岛素分泌β细胞增殖以及胰岛素合成和分泌所必需的。此外，已经发现PERK信号传导是决定特定类型肿瘤的生长和血管生成的重要因素，并且归因于PERK依赖性调节缺氧应激反应。在本报告中，我们研究了PERK在胰岛素瘤发展中调节转化β细胞增殖和血管生成的作用。在诱导型启动子的控制下，将SV40大T抗原（Tag）遗传引入Perk KO小鼠的胰岛素分泌β细胞中。测定肿瘤生长和细胞增殖的相关参数。在晚期胰岛素瘤中，确定了血管分布的程度。Perk缺陷小鼠中胰岛素瘤的形成和生长被显著消融，肿瘤数量少得多，平均比野生型对照小鼠小38倍。在与肿瘤生长减少相关的Perk缺陷小鼠中消除了β细胞增殖。在Perk缺陷小鼠中出现的少量大的包裹性胰岛素瘤中，我们发现与野生型小鼠中类似大小的胰岛素瘤相比，肿瘤血管分布显著减少。尽管Perk缺陷小鼠的胰岛素瘤生长在很大程度上受损，但T抗原诱导足以增加β细胞群，以挽救这些小鼠中的低胰岛素血症和糖尿病。我们得出结论，PERK在β细胞胰岛素瘤的发展中有两个作用，首先是在胰岛增生的初始过渡期间支持快速细胞增殖，然后在晚期包膜肿瘤的进展期间促进血管生成。
PERK eIF2α 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.
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影响因子：
10.5
作者：
Naik, P;Karrim, J;Hanahan, D
通讯作者：
Hanahan, D
DOI：
10.1073/pnas.90.1.232
发表时间：
1993-01-01
影响因子：
11.1
作者：
MEURS, EF;GALABRU, J;HOVANESSIAN, AG
通讯作者：
HOVANESSIAN, AG
影响因子：
8
作者：
Martín, J;Hunt, SL;Barbacid, M
通讯作者：
Barbacid, M
影响因子：
11.4
作者：
Bi, MX;Naczki, C;Koumenis, C
通讯作者：
Koumenis, C
影响因子：
5.6
作者：
Wei, Jianwen;Sheng, Xiaoyi;Cavener, Douglas R.
通讯作者：
Cavener, Douglas R.