CAMP-dependent protein kinase types I and II differentially regulate cAMP response element-mediated gene expression - Implications for neuronal responses to ethanol
CAMP-dependent protein kinase types I and II differentially regulate cAMP response element-mediated gene expression - Implications for neuronal responses to ethanol
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DOI：
10.1074/jbc.m112107200
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发表时间：
2002-05-24
影响因子：
4.8
通讯作者：
Diamond, I
中科院分区：
文献类型：
--
作者：
Constantinescu, A;Gordon, AS;Diamond, I
我们已经表明，乙醇诱导cAMP依赖性蛋白激酶（PKA）易位到细胞核，cAMP反应元件结合蛋白（CREB）磷酸化，cAMP反应元件介导的基因转录在NG 108 -15细胞。然而，很少有人知道哪些PKA类型调节这一过程。我们在这里表明，在基础条件下NG 108 -15细胞含有I型PKA（CbetaRIBeta）主要在胞质溶胶和H型PKA（CalphaRIBeta）的颗粒和核馏分。I型和H型PKA的拮抗剂均抑制毛喉素和乙醇诱导的cAMP反应元件介导的基因转录。然而，只有II型PKA拮抗剂抑制毛喉素诱导的Cot和乙醇诱导的Calpha和RIIbeta易位到细胞核和CREB磷酸化; I型拮抗剂没有效果。我们的数据表明，毛喉素和乙醇诱导的CREB磷酸化和基因激活的差异介导的两种类型的PKA。我们认为II型PKA在细胞核中移位和激活，并诱导CREB磷酸化，这是基因转录所必需的，但还不够。相比之下，I型PKA在细胞质中被激活，开启下游途径，激活与磷酸化CREB相互作用的其他转录辅因子以诱导基因转录。
We have shown that ethanol induces translocation of cAMP-dependent protein kinase (PKA) to the nucleus, cAMP response element-binding protein (CREB) phosphorylation, and cAMP response element-mediated gene transcription in NG108-15 cells. However, little is known about which PKA types regulate this process. We show here that under basal conditions NG108-15 cells contain type I PKA (CbetaRIbeta) primarily in cytosol and type H PKA (CalphaRIIbeta) in the particulate and nuclear fractions. Antagonists of both type I and type H PKA inhibit forskolin- and ethanol-induced cAMP response element-mediated gene transcription. However, only the typeII PKA antagonist inhibits forskolin-induced Cot and ethanol-induced Calpha and RIIbeta translocation to the nucleus and CREB phosphorylation; the type I antagonist is without effect. Our data suggest that forskolin- and ethanol-induced CREB phosphorylation and gene activation are differentially mediated by the two types of PKA. We propose that type II PKA is translocated and activated in the nucleus and induces CREB phosphorylation that is necessary but not sufficient for gene transcription. By contrast, type I PKA is activated in the cytoplasm, turning on a downstream pathway that activates other transcription cofactors that interact with phosphorylated CREB to induce gene transcription.