Metabolic consequences of securin disruption

描述(申请人提供)：细胞周期依赖的Securin蛋白通过抑制分离素功能来调节姐妹染色单体的分离。我们从大鼠垂体瘤细胞中分离并鉴定了垂体肿瘤转化基因(PTTG)，该基因与酵母Securin在功能上具有同源性。PTTG在多种肿瘤组织中过表达，在一些正常复制组织(包括睾丸、淋巴细胞)中也有过表达。当PTTG基因缺失时，所得到的基因敲除小鼠是存活的、有生育能力的，并表现出脾和睾丸发育不良以及血小板减少。令人惊讶的是，6个月后，雄性PTTG-/-小鼠没有体重增加，出现严重的高血糖、低胰岛素血症和低瘦素血症，胰岛素敏感性保持不变。在初步实验中，胰岛β细胞表现为发育不良，胰岛胰岛素免疫反应减弱，没有自身免疫性胰岛参与的证据。本研究旨在通过研究胰岛素的转录、分泌和作用、脂肪细胞激素的调节、胰岛β细胞的发育和复制以及胰腺的再生来研究哺乳动物Securin在胰岛β细胞功能中的作用。由于Securin缺乏型糖尿病仅限于雄性小鼠，完整的或切除性腺的PTTG-/-动物将用性类固醇治疗，并评估它们对血糖和胰腺功能的影响。这些研究强调了细胞周期调节蛋白在胰岛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，并为糖尿病的一种新的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.