ESTROGEN ACTION VIA THE CAMP SIGNALING PATHWAY - STIMULATION OF ADENYLATE-CYCLASE AND CAMP-REGULATED GENE-TRANSCRIPTION
ESTROGEN ACTION VIA THE CAMP SIGNALING PATHWAY - STIMULATION OF ADENYLATE-CYCLASE AND CAMP-REGULATED GENE-TRANSCRIPTION
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DOI：
10.1073/pnas.91.18.8517
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发表时间：
1994-08-30
影响因子：
11.1
通讯作者：
KATZENELLENBOGEN, BS
中科院分区：
文献类型：
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作者：
ARONICA, SM;KRAUS, WL;KATZENELLENBOGEN, BS
据信，雌激素通过其受体与染色质的直接相互作用发挥其大部分作用，在培养的靶乳腺癌细胞和子宫细胞以及体内完整子宫中发现了增加cAMP的作用。极低浓度的雌二醇（在晚上10点达到峰值的一半）和其他生理上活跃的雌激素和抗雌激素可引起细胞内cAMP的增加，但不受无活性的雌激素立体异构体的影响。这些cAMP的增加是由于膜腺苷酸环化酶活性的增强，其机制不涉及激素的基因组作用（不被RNA和蛋白质合成抑制剂阻断）。雌激素刺激的cAMP水平足以激活含有cAMP应答元件的基因和报告质粒结构的转录。我们的研究结果证明了雌激素的非基因组作用，包括激活一个重要的第二信使信号系统，并表明雌激素对cAMP的调节可能提供了一种额外的机制，通过这种类固醇激素可以改变基因的表达。
Estrogenic hormones, believed to exert most of their effects via the direct interaction of their receptors with chromatin, are found to increase cAMP in target breast cancer and uterine cells in culture and in the intact uterus in vivo. Increases in intracellular cAMP are evoked by very low concentrations of estradiol (half maximal at 10 pM) and by other physiologically active estrogens and antiestrogens, but not by an inactive estrogen stereoisomer. These increases in cAMP result from enhanced membrane adenylate cyclase activity by a mechanism that does not involve genomic actions of the hormones (are not blocked by inhibitors of RNA and protein synthesis). The estrogen-stimulated levels of cAMP are sufficient to activate transcription from cAMP response element-containing genes and reporter plasmid constructs. Our findings document a nongenomic action of estrogenic hormones that involves the activation of an important second-messenger signaling system and suggest that estrogen regulation of cAMP may provide an additional mechanism by which this steroid hormone can alter the expression of genes.