...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2.
【24h】

Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2.

机译：cAMP通过诱导凋亡蛋白抑制剂（IAP）-2抑制正常和转化的肠上皮细胞的凋亡。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Cyclooxygenase (COX)-2, a rate-limiting enzyme of prostaglandin (PG) production, is overexpressed in colorectal adenomas and adenocarcinomas, and its inhibition by nonsteroidal antiinflammatory drugs protects against colorectal cancer. Mechanisms of cancer promotion by COX-2 are not fully understood, but signaling through prostaglandin (PG)E2 receptors is a contributing factor. The major PGE2 receptors on epithelial cells, EP2 and EP4, increase cAMP production, which promotes growth and inhibits apoptosis in some cell types. Here, we show that cAMP agonists, including PGE2, cholera toxin, and a membrane-permeant cAMP analog, protect normal and transformed intestinal epithelial cells from apoptosis induced by diverse stimuli. This protection is associated with cAMP-mediated, rapid induction of cellular inhibitor of apoptosis protein (c-IAP)-2 and delayed induction of LIVIN, but not of six other members of the IAP family. Concurrently and characteristic of IAP functions, the activity, but not generation,of the cleaved form of the central executioner caspase 3 is inhibited. Induction of c-IAP2 expression by cAMP agonists is accompanied by phosphorylation of cAMP response element binding protein and cAMP response element-dependent activation of transcriptional reporters. Furthermore, inhibition of COX-2 in cells overexpressing the enzyme decreases c-IAP2 expression and promotes apoptosis, both of which are reversible by PGE2 addition, suggesting that COX-2-promoted antiapoptosis is mediated by release of PGE2 and subsequent cAMP-dependent c-IAP2 induction. These results help to explain the cancer chemoprotective effects of nonsteroidal antiinflammatory drugs by defining a mechanism through which cAMP signaling can promote the development of colorectal and possibly other epithelial cancers by means of disruption of normal apoptotic processes.
机译：环氧合酶（COX）-2是前列腺素（PG）产生的限速酶，在结直肠腺瘤和腺癌中过表达，非甾体类抗炎药对其抑制可预防结直肠癌。还没有完全了解COX-2促进癌症的机制，但通过前列腺素（PG）E2受体的信号传导是一个促成因素。上皮细胞上的主要PGE2受体EP2和EP4增加cAMP的产生，从而促进某些细胞类型的生长并抑制细胞凋亡。在这里，我们显示了cAMP激动剂，包括PGE2，霍乱毒素和膜渗透性cAMP类似物，可以保护正常的和转化的肠上皮细胞免受各种刺激诱导的细胞凋亡。这种保护与cAMP介导的细胞凋亡蛋白（c-IAP）-2抑制剂的快速诱导和LIVIN的延迟诱导有关，但与IAP家族的其他六个成员无关。同时，IAP功能的特征是，中枢执行酶胱天蛋白酶3的裂解形式的活性而不是生成受到抑制。 cAMP激动剂诱导c-IAP2表达伴随着cAMP反应元件结合蛋白的磷酸化和cAMP反应元件依赖的转录报道分子的活化。此外，在过表达该酶的细胞中抑制COX-2会降低c-IAP2的表达并促进细胞凋亡，这两者均可通过添加PGE2来逆转，这表明COX-2促进的抗凋亡作用是由PGE2的释放和随后依赖cAMP的c介导的。 -IAP2诱导。这些结果通过定义一种机制来解释非甾体类抗炎药的癌症化学保护作用，通过该机制，cAMP信号传导可通过破坏正常的凋亡过程而促进结直肠癌和其他上皮癌的发展。

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