Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK
Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK
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DOI：
10.1074/jbc.m313346200
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发表时间：
2004-06-18
影响因子：
4.8
通讯作者：
Insel, PA
中科院分区：
文献类型：
--
作者：
Nishihara, H;Hwang, M;Insel, PA
我们最近报道，cAMP 抑制结肠癌细胞的凋亡，并通过 cAMP 反应元件 (CRE) 诱导细胞凋亡蛋白抑制剂 2 (c-IAP2)，这表明了非甾体抗炎药化学预防结肠癌的机制。在这项研究中，我们使用 T84 人结肠癌细胞来确定 cAMP 增加诱导 c-IAP2 表达的途径。用几种不同的 cAMP 激动剂治疗可刺激 CRE 结合蛋白 (CREB) 的磷酸化，并以 CREB 依赖性方式激活 c-IAP2 的表达。药物抑制剂的研究表明，CREB 的 cAMP 依赖性磷酸化需要 ERK1/2 和 p38 MAPK 的激活，但在很大程度上独立于蛋白激酶 A。使用特定抑制剂的免疫印迹和转录报告分析以及 MEK1 和 MKK3 的组成型活性形式的表达表明，cAMP 诱导的 c-IAP2 主要通过 ERK1/2 和 p38 MAPK 进行调节，并表明 p90 核糖体蛋白的参与S6 激酶、丝裂原和应激反应激酶 1 也是如此。与这些结果一致，我们发现 ERK1/2 和 p38 MAPK 抑制剂治疗可阻断 cAMP 依赖性细胞凋亡抑制。我们得出的结论是，cAMP 可以通过 CREB 磷酸化和 CRE 依赖性转录，以涉及 ERK1/2 和 p38 MAPK 激活的方式诱导结肠癌细胞中 c-IAP2 表达。这些结果强调，蛋白激酶 A 以外的激酶的激活可以介导增加 cAMP 的药物的作用，特别是在 CREB 依赖性事件的调节中。
We recently reported that cAMP suppresses apoptosis in colon cancer cells and induces cellular inhibitor of apoptosis protein-2 (c-IAP2) via a cAMP-responsive element (CRE), suggesting a mechanism for chemoprevention of colon cancer by non-steroidal anti-inflammatory drugs. In this study, we used T84 human colon cancer cells to define the pathway by which increases in cAMP induce c-IAP2 expression. Treatment with several different cAMP agonists stimulated phosphorylation of CRE-binding protein (CREB) and activated expression of c-IAP2 in a CREB-dependent manner. Studies with pharmacological inhibitors revealed that cAMP-dependent phosphorylation of CREB required activation of ERK1/2 and p38 MAPK but was largely independent of protein kinase A. Immunoblots and transcriptional reporter assays using specific inhibitors, as well as expression of constitutively active forms of MEK1 and MKK3, showed that c-IAP2 induction by cAMP is regulated predominantly through ERK1/2 and p38 MAPK and suggested involvement of p90 ribosomal protein S6 kinase and mitogen and stress response kinase-1 as well. Consistent with those results, we found that cAMP-dependent suppression of apoptosis was blocked by treatment with inhibitors of ERK1/2 and p38 MAPK. We conclude that cAMP can induce c-IAP2 expression in colon cancer cells through CREB phosphorylation and CRE-dependent transcription in a manner that involves activation of ERK1/2 and p38 MAPK. These results emphasize that activation of kinases other than protein kinase A can mediate the actions of agents that increase cAMP, particularly in the regulation of CREB-dependent events.