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首页> 外文期刊>Molecular and Cellular Biology >A refractory phase in cyclic AMP-responsive transcription requires down regulation of protein kinase A.
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A refractory phase in cyclic AMP-responsive transcription requires down regulation of protein kinase A.

机译：环状AMP应答转录中的难治期需要下调蛋白激酶A。

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Cyclic AMP (cAMP) stimulates the expression of numerous genes through the protein kinase A (PK-A)-mediated phosphorylation of the nuclear factor CREB at Ser-133 (G. A. Gonzalez and M. R. Montminy, Cell 59:675-680, 1989). Like other signal transduction pathways, cAMP induces gene expression with burst-attenuation kinetics; cAMP-dependent transcription and CREB phosphorylation peak within 30 min and decline steadily over the next 4 to 6 h via the protein phosphatase 1-mediated dephosphorylation of CREB (M. Hagiwara, A. Alberts, P. Brindle, J. Meinkoth, J. Feramisco, T. Deng, M. Karin, S. Shenolikar, and M. Montminy, Cell 70:105-113, 1992). Here we characterize a third phase in cAMP-responsive transcription--a refractory period during which hormone-treated cells become transcriptionally unresponsive to subsequent stimulation by cAMP. This refractory period begins 6 to 8 h after stimulation and lasts 3 to 5 days after the removal of hormone. In contrast to the earlier attenuation phase, transcription of cAMP-responsive genes during the refractory period is not restored by inhibitors of protein phosphatase 1 activity. Rather, the establishment and maintenance of this phase rely on a marked reduction in PK-A catalytic subunit expression at the translational level. As overexpression of C-subunit protein can reactive transcription of cAMP-responsive genes during the refractory period, our results suggest that hormone-responsive cells may stimulate, attenuate, and then silence signal-dependent genes through distinct regulatory mechanisms.
机译：环AMP（cAMP）通过蛋白激酶A（PK-A）介导的Ser-133核因子CREB的磷酸化刺激许多基因的表达（G.A.Gonzalez和M.R.Montminy，Cell 59：675-680，1989）。像其他信号转导途径一样，cAMP诱导具有突发衰减动力学的基因表达。 cAMP依赖性转录和CREB磷酸化在30分钟内达到峰值，并在接下来的4至6小时内通过蛋白质磷酸酶1介导的CREB的去磷酸化而稳定下降（M.Hagiwara，A.Alberts，P.Brindle，J.Meinkoth，J. Feramisco，T.Deng，M.Karin，S.Shenolikar和M.Montminy，Cell 70：105-113，1992）。在这里，我们表征了cAMP响应转录的第三阶段-难治期，在此期间激素处理的细胞对cAMP的后续刺激失去转录响应。该不应期在刺激后6至8小时开始，并在激素去除后持续3至5天。与较早的衰减阶段相反，在不应期不能通过蛋白磷酸酶1活性抑制剂恢复cAMP反应基因的转录。而是，此阶段的建立和维持依赖于翻译水平上PK-A催化亚基表达的显着降低。由于C亚基蛋白的过度表达可以在不应期内反应cAMP反应性基因的转录，因此我们的结果表明激素反应性细胞可以通过独特的调控机制刺激，减弱然后沉默信号依赖性基因。

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