公开(公告)号：US20140157444A1

公开(公告)日：2014-06-05

申请号：US14116539

申请日：2012-04-27

申请人： Satish Kumar ,  Vijay Pratap Singh

发明人： Satish Kumar ,  Vijay Pratap Singh

IPC分类号： A61K49/00

CPC分类号： A61K49/0008 ,  A01K67/0276 ,  A01K2217/072 ,  A01K2227/105 ,  A01K2267/0331 ,  A01K2267/0362 ,  C07K14/47 ,  C07K2319/41 ,  C07K2319/43 ,  C12N2710/10043

摘要： WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of the enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was down regulated in the mutant islets overexpression of WDR13 in the pancreatic MIN6 cell line resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Co-immunoprecipitation experiments showed that this protein interacts with estrogen receptors and various HDACs. We provide evidence to show that WDR13 can regulate estrogen receptors-mediated transcription both in HDAC-dependent and HDAC-independent manner. Given the higher insulin levels, better glucose clearance and the lack of insulin resistance in WDR13 deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes.

摘要翻译： WD重复蛋白是非常多样化的，但这些是参与广泛细胞功能的结构相关蛋白。 WDR13，这个家庭的成员，从鱼类保存到人类，并定位到核心。 为了了解Wdr​​13基因的体内功能，我们创建并表征了缺乏该基因的突变小鼠株。 由于增强的β细胞增殖，突变小鼠具有较高的血清胰岛素水平和胰岛素的增加。 虽然已知的细胞周期抑制剂p21在胰岛MIN6细胞系中突变型胰岛过表达WDR13中下调，导致p21上调，伴随着细胞增殖的延迟。 我们建议WDR13是胰腺β细胞增殖的新型负调节因子。 共免疫沉淀实验显示，该蛋白质与雌激素受体和各种HDAC相互作用。 我们提供证据表明，WDR13可以调节雌激素受体介导的转录，无论是HDAC依赖型还是HDAC独立型。 鉴于WDR13缺陷小鼠胰岛素水平升高，葡萄糖清除率更高，胰岛素抵抗不足，我们建议该蛋白可能是改善糖尿病中糖代谢紊乱的潜在候选药物靶点。

公开(公告)号：US09198986B2

公开(公告)日：2015-12-01

申请号：US14116539

申请日：2012-04-27

申请人： Satish Kumar ,  Vijay Pratap Singh

发明人： Satish Kumar ,  Vijay Pratap Singh

IPC分类号： C12N15/00 ,  A61K49/00 ,  A01K67/027 ,  C07K14/47

CPC分类号： A61K49/0008 ,  A01K67/0276 ,  A01K2217/072 ,  A01K2227/105 ,  A01K2267/0331 ,  A01K2267/0362 ,  C07K14/47 ,  C07K2319/41 ,  C07K2319/43 ,  C12N2710/10043

摘要： WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of the enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was down regulated in the mutant islets overexpression of WDR13 in the pancreatic MIN6 cell line resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Co-immunoprecipitation experiments showed that this protein interacts with estrogen receptors and various HDACs. We provide evidence to show that WDR13 can regulate estrogen receptors-mediated transcription both in HDAC-dependent and HDAC-independent manner. Given the higher insulin levels, better glucose clearance and the lack of insulin resistance in WDR13 deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes.

摘要翻译： WD重复蛋白是非常多样化的，但这些是参与广泛细胞功能的结构相关蛋白。 WDR13，这个家庭的成员，从鱼类保存到人类，并定位到核心。 为了了解Wdr​​13基因的体内功能，我们创建并表征了缺乏该基因的突变小鼠株。 由于增强的β细胞增殖，突变小鼠具有较高的血清胰岛素水平和胰岛素的增加。 虽然已知的细胞周期抑制剂p21在胰岛MIN6细胞系中突变型胰岛过表达WDR13中下调，导致p21上调，伴随着细胞增殖的延迟。 我们建议WDR13是胰腺β细胞增殖的新型负调节因子。 共免疫沉淀实验显示，该蛋白质与雌激素受体和各种HDAC相互作用。 我们提供证据表明，WDR13可以调节雌激素受体介导的转录，无论是HDAC依赖型还是HDAC独立型。 鉴于WDR13缺陷小鼠胰岛素水平升高，葡萄糖清除率更高，胰岛素抵抗不足，我们建议该蛋白可能是改善糖尿病中糖代谢紊乱的潜在候选药物靶点。