Metabolic consequences of securin disruption

描述（申请人提供）：细胞周期依赖性securin蛋白通过抑制分离蛋白功能调节姐妹染色单体分离。我们从大鼠垂体瘤细胞中分离并鉴定了垂体瘤转化基因（PTTG），PTTG在功能上与酵母securin同源。PTTG在几种肿瘤类型中过表达，并且在一些正常复制组织（包括睾丸、睾丸细胞）中也过表达。当PTTG基因被删除时，产生的敲除小鼠是可行的，可生育的，并表现出脾脏和睾丸发育不全和血小板减少症。令人惊讶的是，6个月后，雄性PTTG -/-小鼠没有体重增加，没有出现严重的高血糖症、低胰岛素血症和低瘦素血症，胰岛素敏感性完好无损。在初步实验中，胰腺β细胞出现发育不良，胰岛胰岛素免疫反应性降低，没有证据表明自身免疫性胰岛参与。该提案旨在通过评估胰岛素的转录、分泌和作用、脂肪细胞激素的调节以及评估胰腺β细胞的发育和复制以及胰腺再生来研究哺乳动物securin在胰腺β细胞功能中的作用。由于securin缺陷型糖尿病仅限于雄性小鼠，因此将用性类固醇治疗完整或性腺切除的PTTG -/-动物，并评估其对胰腺和胰腺功能的影响。这些研究强调了细胞周期调节蛋白在胰腺β细胞发育和功能中的作用。在这种独特的遗传背景下，这些实验将securin确定为胰腺细胞功能的关键因素，并为糖尿病的新单基因病因提供了见解。

DESCRIPTION (provided by applicant): Cell cycle-dependent securin proteins regulate sister chromatid separation by inhibiting separin function. We isolated and have characterized pituitary tumor transforming gene (PTTG) from rat pituitary tumor cells, and PTTG is functionally homologous to yeast securin. PTTG is overexpressed in several tumor types, and also in some normal replicating tissues (including testis, lympocytes). When the PTTG gene was deleted, resultant knockout mice were viable, fertile and exhibited splenic and testicular hypoplasia and thrombocytopenia. Surprisingly, after 6 months, male PTTG -/- mice do not gain weight, develop profound hyperglycemia, hypo-insulinemia, and hypo-leptinemia with intact insulin sensitivity. In preliminary experiments, pancreatic beta cells appear hypoplastic with diminished islet insulin immunoreactivity, and no evidence for autoimmune islet involvement. This proposal aims to study the role of mammalian securin in pancreatic beta cell function by assessing insulin transcription, secretion and action, regulation of adipocyte hormones and assessment of pancreatic beta cell development and replication, and pancreatic regeneration. As securin-deficient diabetes is restricted to male mice, intact or gonadectomized PTTG -/- animals will be treated with sex steroids, and their impact on glycemia and pancreatic function assessed. These studies highlight the role of a cell cycle-regulating protein in pancreatic beta cell development and function. In the context of this unique genetic background, these experiments identify securin as a critical factor for pancreatic cell function and provide insights into a novel monogenic cause of diabetes.