Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway.
Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway.
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DOI：
10.1016/j.biopha.2011.03.009
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Nonnemacher MR
中科院分区：
文献类型：
--
作者：
Banerjee A;Pirrone V;Wigdahl B;Nonnemacher MR
环磷酸腺苷（cAMP）依赖性信号通路指导参与多种神经内分泌、免疫、代谢和发育途径的几种基因的表达。该途径的主要效应物是cAMP反应元件结合（CREB）转录因子家族的成员，特别是CREB-1和cAMP反应元件调节剂（CREM）。这两个基因编码的选择性剪接变异体，作为激活剂或阻遏物的背景和位置特异性的方式。虽然β-趋化因子受体CC趋化因子受体5（CCR 5）已在骨髓中的祖细胞上被鉴定，但协调其表达的调节机制尚未完全了解。先前的报道已经鉴定了CCR 5启动子中推定的cAMP应答元件，并且描述了cAMP在CCR 5表达中的抑制作用。在这项研究中，CD 34 + CD 4 + CCR 5+人骨髓祖细胞系TF-1被用来研究CCR 5转录的详细动力学响应于细胞内cAMP水平的升高和潜在的分子事件。我们假设，在TF-1细胞中，CCR 5转录遵循不对称的正弦模式，这与激活剂pCREB-1-α，Δ与抑制剂pCREM-α，β亚型的比例的蛋白激酶A依赖性交替变化平行。然而，升高的CCR 5 mRNA水平与R5人类免疫缺陷病毒1型（HIV-1）毒株的感染性增强无关。我们的研究结果提供了关键的洞察力，在祖细胞中的cAMP-CCR 5轴的精确机制，并提出了有趣的问题，其在HIV-1感染的功能作用。
The cyclic adenosine monophosphate (cAMP)-dependent signaling pathway directs the expression of several genes involved in diverse neuroendocrine, immune, metabolic, and developmental pathways. The primary effectors of this pathway are members of the cAMP response element binding (CREB) family of transcription factors, in particular the CREB-1 and cAMP response element modulator (CREM). Both these genes encode alternative splice variants that serve as activators or repressors in a context- and position-specific manner. Although the β- chemokine receptor CC chemokine receptor 5 (CCR5) has been identified on progenitor cells in the bone marrow, the regulatory mechanisms orchestrating its expression are not fully understood. Previous reports have identified putative cAMP response elements in the CCR5 promoter and have described a suppressive role of cAMP in CCR5 expression. In this study, the CD34+CD4+CCR5+ human bone marrow progenitor cell line TF-1 was used to investigate the detailed kinetics of CCR5 transcription in response to the elevation of intracellular cAMP levels and the underlying molecular events. We hypothesize that CCR5 transcription follows an asymmetrical sinusoidal pattern in TF-1 cells that parallels a protein kinase A-dependent alternating change in the ratio of activator pCREB-1-α,Δ to repressor pCREM-α,β isoforms. However, elevated CCR5 mRNA levels do not correlate with enhancement in infectivity with respect to the R5 human immunodeficiency virus type 1 (HIV-1) strain. Our results lend critical insight into the precise mechanism governing the cAMP-CCR5 axis in progenitor cells and pose interesting questions regarding its functional role in HIV-1 infection.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.8
作者：
Craig, JC;Schumacher, MA;Goodman, RH
通讯作者：
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DOI：
10.1196/annals.1395.014
发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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