A refractory phase in cyclic AMP-responsive transcription requires down regulation of protein kinase A.
A refractory phase in cyclic AMP-responsive transcription requires down regulation of protein kinase A.
复制标题
环 AMP 响应转录的不应期需要下调蛋白激酶 A。
DOI：
10.1128/mcb.15.3.1826
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发表时间：
1995
影响因子：
5.3
通讯作者：
Montminy,M
中科院分区：
文献类型：
--
作者：
Armstrong,R;Wen,W;Meinkoth,J;Taylor,S;Montminy,M
环磷酸腺苷(CAMP)通过蛋白激酶A(PK-A)介导的核因子CREB在Ser-133处的磷酸化来刺激许多基因的表达(G.A.Gonzalez和M.R.Montminy，Cell 59：675-680，)。与其他信号转导途径一样，cAMP诱导基因表达具有突发性衰减动力学；cAMP依赖的转录和CREB的磷酸化在30分钟内达到峰值，并在接下来的4到6小时内通过蛋白磷酸酶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.邓，M.Karin，S.Shenolikar和M.Montminy，Cell 70：105-113,1992)。在这里，我们描述了cAMP反应转录的第三个阶段--在此期间，激素处理的细胞在转录上对cAMP随后的刺激变得不反应。这一不应期在刺激后6-8小时开始，在激素去除后持续3-5天。与早期的衰减期不同，不应期cAMP反应基因的转录不能被蛋白磷酸酶1活性的抑制剂恢复。相反，这一阶段的建立和维持依赖于翻译水平上PK-A催化亚基表达的显著减少。由于C亚单位蛋白的过度表达可以在不应期对cAMP反应基因进行转录反应，我们的结果提示激素反应细胞可能通过不同的调节机制刺激、减弱和沉默信号依赖的基因。
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.