...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular and Cellular Biology >Increased Pancreatic β-Cell Proliferation Mediated by CREB Binding Protein Gene Activation
【24h】

Increased Pancreatic β-Cell Proliferation Mediated by CREB Binding Protein Gene Activation

机译：CREB结合蛋白基因激活介导的胰腺β细胞增殖增加

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The cyclic AMP (cAMP) signaling pathway is central in β-cell gene expression and function. In the nucleus, protein kinase A (PKA) phosphorylates CREB, resulting in recruitment of the transcriptional coactivators p300 and CREB binding protein (CBP). CBP, but not p300, is phosphorylated at serine 436 in response to insulin action. CBP phosphorylation disrupts CREB-CBP interaction and thus reduces nuclear cAMP action. To elucidate the importance of the cAMP-PKA-CREB-CBP pathway in pancreatic β cells specifically at the nuclear level, we have examined mutant mice lacking the insulin-dependent phosphorylation site of CBP. In these mice, the CREB-CBP interaction is enhanced in both the absence and presence of cAMP stimulation. We found that islet and β-cell masses were increased twofold, while pancreas weights were not different from the weights of wild-type littermates. β-Cell proliferation was increased both in vivo and in vitro in isolated islet cultures. Surprisingly, glucose-stimulated insulin secretion from perfused, isolated mutant islets was reduced. However, β-cell depolarization with KCl induced similar levels of insulin release from mutant and wild-type islets, indicating normal insulin synthesis and storage. In addition, transcripts of pgc1a, which disrupts glucose-stimulated insulin secretion, were also markedly elevated. In conclusion, sustained activation of CBP-responsive genes results in increased β-cell proliferation. In these β cells, however, glucose-stimulated insulin secretion was diminished, resulting from concomitant CREB-CBP-mediated pgc1a gene activation.
机译：环状AMP（cAMP）信号通路是β细胞基因表达和功能的核心。在细胞核中，蛋白激酶A（PKA）使CREB磷酸化，导致募集转录共激活因子p300和 C REB b inding p rotein（ CBP）。响应胰岛素作用，CBP而不是p300在丝氨酸436磷酸化。 CBP磷酸化破坏了CREB-CBP的相互作用，从而降低了核cAMP的作用。为了阐明在胰腺β细胞中cAMP-PKA-CREB-CBP途径的重要性，特别是在核水平上，我们检查了缺少CBP胰岛素依赖性磷酸化位点的突变小鼠。在这些小鼠中，在不存在和存在cAMP刺激的情况下，CREB-CBP相互作用都会增强。我们发现，胰岛和β细胞的质量增加了两倍，而胰腺的重量与野生型同窝仔的重量没有差异。在分离的胰岛培养物中，β-细胞增殖在体内和体外均增加。令人惊讶地，减少了来自灌注的，分离的突变胰岛的葡萄糖刺激的胰岛素分泌。但是，用KCl进行的β细胞去极化诱导了类似水平的胰岛素从突变和野生型胰岛的释放，表明胰岛素的合成和储存正常。另外，破坏葡萄糖刺激的胰岛素分泌的 pgc1a 的转录本也显着升高。总之，持续激活CBP反应基因会导致β细胞增殖增加。然而，在这些β细胞中，葡萄糖刺激的胰岛素分泌减少，这是由CREB-CBP介导的 pgc1a 基因激活引起的。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号