Chesnokova Vera, Wong Chris, Zonis Svetlana, Gruszka Anna, Wawrowsky Kolja, Ren Song-Guang, Benshlomo Anat, Yu Run
Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90048, USA.
Endocrinology. 2009 Jun;150(6):2603-10. doi: 10.1210/en.2008-0972. Epub 2009 Feb 12.
Pituitary tumor transforming gene (PTTG) encodes a securin protein critical in regulating chromosome separation. PTTG-null (PTTG(-/-)) mice exhibit pancreatic beta-cell hypoplasia and insulinopenic diabetes. We tested whether PTTG deletion causes beta-cell senescence, resulting in diminished beta-cell mass. We examined beta-cell mass, proliferation, apoptosis, neogenesis, cell size, and senescence in PTTG(-/-) and WT mice from embryo to young adulthood before diabetes is evident. The roles of cyclin-dependent kinase inhibitors and DNA damage in the pathogenesis of diabetes in PTTG(-/-) mice were also addressed. Relative beta-cell mass in PTTG(-/-) mice began to decrease at 2-3 wk, whereas beta-cell proliferation rate was initially normal but decreased in PTTG(-/-) mice beginning at 2 months. Apoptosis was also much more evident in PTTG(-/-) mice. At 1 month, beta-cell neogenesis was robust in wild-type mice but was absent in PTTG(-/-) mice. In addition, the size of beta-cells became larger and macronuclei were prominent in PTTG(-/-) animals. Senescence-associated beta-galactosidase was also active in PTTG(-/-) beta-cells at 1 month. Cyclin-dependent kinase inhibitor p21 was progressively up-regulated in PTTG(-/-) islets, and p21 deletion partially rescued PTTG(-/-) mice from development of diabetes. mRNA array showed that DNA damage-associated genes were activated in PTTG(-/-) islets. We conclude that beta-cell apoptosis and senescence contribute to the diminished beta-cell mass in PTTG(-/-) mice, likely secondary to DNA damage. Our results also suggest that ductal progenitor beta-cells are exhausted by excessive neogenesis induced by apoptosis in PTTG(-/-) mice.
垂体肿瘤转化基因（PTTG）编码一种在调节染色体分离中起关键作用的分离酶抑制蛋白。PTTG基因敲除（PTTG(-/-)）小鼠表现出胰腺β细胞发育不全和胰岛素分泌不足型糖尿病。我们测试了PTTG缺失是否会导致β细胞衰老，从而导致β细胞数量减少。我们检查了PTTG(-/-)和野生型（WT）小鼠从胚胎期到成年早期（在糖尿病明显出现之前）的β细胞数量、增殖、凋亡、新生、细胞大小和衰老情况。还探讨了细胞周期蛋白依赖性激酶抑制剂和DNA损伤在PTTG(-/-)小鼠糖尿病发病机制中的作用。PTTG(-/-)小鼠的相对β细胞数量在2 - 3周时开始减少，而β细胞增殖率最初正常，但从2个月开始在PTTG(-/-)小鼠中下降。凋亡在PTTG(-/-)小鼠中也更为明显。在1个月时，野生型小鼠的β细胞新生旺盛，但PTTG(-/-)小鼠中不存在。此外，PTTG(-/-)动物的β细胞体积变大，大核突出。衰老相关的β - 半乳糖苷酶在1个月时的PTTG(-/-)β细胞中也有活性。细胞周期蛋白依赖性激酶抑制剂p21在PTTG(-/-)胰岛中逐渐上调，p21缺失部分挽救了PTTG(-/-)小鼠的糖尿病发展。mRNA芯片显示DNA损伤相关基因在PTTG(-/-)胰岛中被激活。我们得出结论，β细胞凋亡和衰老导致了PTTG(-/-)小鼠中β细胞数量减少，可能继发于DNA损伤。我们的结果还表明，PTTG(-/-)小鼠中导管祖细胞β细胞因凋亡诱导的过度新生而耗竭。
