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首页> 外文期刊>Molecular and Cellular Biology >Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation.
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Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation.

机译：核蛋白磷酸酶2A使蛋白激酶A磷酸化的CREB去磷酸化，并调节CREB转录刺激。

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Cyclic AMP (cAMP)-dependent protein kinase A (PKA) stimulates the transcription of many eucaryotic genes by catalyzing the phosphorylation of the cAMP-regulatory element binding protein (CREB). Conversely, the attenuation or inhibition of cAMP-stimulated gene transcription would require the dephosphorylation of CREB by a nuclear protein phosphatase. In HepG2 cells treated with the protein serine/threonine (Ser/Thr) phosphatase inhibitor okadaic acid, dibutyryl-cAMP-stimulated transcription from the phosphoenolpyruvate carboxykinase (PEPCK) promoter was enhanced over the level of PEPCK gene transcription observed in cells treated with dibutyryl-cAMP alone. This process was mediated, at least in part, by a region of the PEPCK promoter that binds CREB. Likewise, okadaic acid prevents the dephosphorylation of PKA-phosphorylated CREB in rat liver nuclear extracts and enhances the ability of PKA to stimulate transcription from the PEPCK promoter in cell-free reactions. The ability of okadaic acid to enhance PKA-stimulated transcription in vitro was entirely dependent on the presence of CREB in the reactions. The phospho-CREB (P-CREB) phosphatase activity present in nuclear extracts coelutes with protein Ser/Thr phosphatase type 2A (PP2A) on Mono Q, amino-hexyl Sepharose, and heparin agarose columns and was chromatographically resolved from nuclear protein Ser/Thr-phosphatase type 1 (PP1). Furthermore, P-CREB phosphatase activity in nuclear extracts was unaffected by the heat-stable protein inhibitor-2, which is a potent and selective inhibitor of PP1. Nuclear PP2A dephosphorylated P-CREB 30-fold more efficiently than did nuclear PP1. Finally, when PKA-phosphorylated CREB was treated with immunopurified PP2A and PP1, the PP2A-treated CREB did not stimulate transcription from the PEPCK promoter in vitro, whereas the PP1-treated CREB retained the ability to stimulate transcription. Nuclear PP2A appears to be the primary phosphatase that dephosphorylates PKA-phosphorylated CREB.
机译：环状AMP（cAMP）依赖性蛋白激酶A（PKA）通过催化cAMP调节元件结合蛋白（CREB）的磷酸化来刺激许多真核基因的转录。相反，cAMP刺激的基因转录的减弱或抑制将要求核蛋白磷酸酶使CREB脱磷酸化。在用丝氨酸/苏氨酸（Ser / Thr）磷酸酶抑制剂冈田酸处理的HepG2细胞中，磷酸二烯丙酯丙酮酸羧激酶（PEPCK）启动子的二丁酰-cAMP刺激的转录水平高于用二丁酰-酪氨酸处理的细胞中观察到的PEPCK基因转录水平。单独使用cAMP。该过程至少部分地由结合CREB的PEPCK启动子的区域介导。同样，冈田酸可防止大鼠肝核提取物中PKA磷酸化的CREB的去磷酸化，并增强PKA在无细胞反应中刺激PEPCK启动子转录的能力。冈田酸在体外增强PKA刺激的转录的能力完全取决于反应中CREB的存在。核提取物中存在的磷酸CR-CREB（P-CREB）磷酸酶活性与Mono Q，氨基己基琼脂糖和肝素琼脂糖柱上的2A型Ser / Thr磷酸酶（PP2A）蛋白共洗脱，并通过色谱分离自核蛋白Ser / Thr分离-1型磷酸酶（PP1）。此外，核提取物中的P-CREB磷酸酶活性不受热稳定蛋白抑制剂2的影响，后者是PP1的一种有效的选择性抑制剂。 PP 2A核的磷酸化P-CREB的效率比PP1核高30倍。最后，当用免疫纯化的PP2A和PP1处理PKA磷酸化的CREB时，PP2A处理的CREB不能在体外刺激PEPCK启动子的转录，而PP1处理的CREB保留了刺激转录的能力。核PP2A似乎是使PKA磷酸化的CREB去磷酸化的主要磷酸酶。

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