Increased pancreatic β-cell proliferation mediated by CREB binding protein gene activation
Increased pancreatic β-cell proliferation mediated by CREB binding protein gene activation
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DOI：
10.1128/mcb.02353-05
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发表时间：
2006-10-01
影响因子：
5.3
通讯作者：
Wondisford, Fredric E.
中科院分区：
文献类型：
--
作者：
Hussain, Mehboob A.;Porras, Delia L.;Wondisford, Fredric E.
环AMP（cAMP）信号传导途径在β细胞基因表达和功能中是中心的。在细胞核中，蛋白激酶A（PKA）磷酸化CREB，导致转录辅激活因子p300和CREB结合蛋白（CBP）的募集。CBP，而不是p300，在丝氨酸436处磷酸化以响应胰岛素作用。CBP磷酸化破坏CRIEB-CBP相互作用，从而降低核cAMP作用。为了阐明cAMP-PKA-CREB-CBP通路在胰腺β细胞中的重要性，特别是在核水平上，我们检查了缺乏CBP的胰岛素依赖性磷酸化位点的突变小鼠。在这些小鼠中，CREB-CBP相互作用在不存在和存在cAMP刺激的情况下均增强。我们发现，胰岛和β细胞质量增加了两倍，而胰腺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，体内和体外β-细胞增殖均增加。令人惊讶的是，葡萄糖刺激的胰岛素分泌灌注，分离的突变体胰岛减少。然而，β-细胞去极化与氯化钾诱导类似水平的胰岛素释放的突变体和野生型胰岛，表明正常的胰岛素合成和储存。此外，破坏葡萄糖刺激的胰岛素分泌的pgc 1a的转录物也显著升高。总之，CBP应答基因的持续激活导致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，这是由于伴随的CREB-CBP介导的pgc 1a基因激活。
The cyclic AMP (cAMP) signaling pathway is central in beta-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 CRIEB-CBP interaction and thus reduces nuclear cAMP action. To elucidate the importance of the cAMP-PKA-CREB-CBP pathway in pancreatic beta 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 beta-cell masses were increased twofold, while pancreas weights were not different from the weights of wild-type littermates. beta-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, beta-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 beta-cell proliferation. In these beta cells, however, glucose-stimulated insulin secretion was diminished, resulting from concomitant CREB-CBP-mediated pgc1a gene activation.