Inhibition of erythroblast growth and fetal hemoglobin production by ribofuranose-substituted adenosine derivatives.
Inhibition of erythroblast growth and fetal hemoglobin production by ribofuranose-substituted adenosine derivatives.
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呋喃核糖取代的腺苷衍生物抑制成红细胞生长和胎儿血红蛋白产生。
DOI：
10.1016/j.bbadis.2008.05.004
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Miller,JefferyL
中科院分区：
文献类型：
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作者：
Bhanu,NatarajanV;Lee,YTerry;Oneal,PatriciaA;Gantt,NicoleM;Aerbajinai,Wulin;Noel,Pierre;Thomas,CraigJ;Miller,JefferyL
在体内，人出生前后胎儿血红蛋白（HbF）表达的抑制会导致镰状细胞和β -地中海贫血综合征的临床表现。最近，一种名为SQ22536的腺苷衍生物分子描述了培养细胞对HbF的抑制作用。本研究利用原代细胞培养模型进一步探讨腺苷衍生物分子对HbF的抑制作用。在胎儿和成人血液中培养的红细胞中，SQ22536显示出生长和HbF表达的下调。在大多数细胞中都注意到对HbF的影响，定量PCR分析证实了其转录机制。筛选实验表明，另外两个名为5 ' -脱氧腺苷和2 ',3 ' -二脱氧腺苷的分子对HbF的作用与SQ22536相当。其他腺苷衍生物分子、腺苷受体结合配体和camp信号调节因子在匹配培养中未能抑制HbF。这些结果表明，结构相关的核糖呋喃糖取代腺苷类似物通过一种未知的机制抑制胎儿和成人红细胞中HbF的表达。
In vivo, inhibition of fetal hemoglobin (HbF) expression in humans around the time of birth causes the clinical manifestation of sickle cell and beta-thalassemia syndromes. Inhibition of HbF among cultured cells was recently described by the adenosine derivative molecule named SQ22536. Here, a primary cell culture model was utilized to further explore the inhibition of HbF by adenosine derivative molecules. SQ22536 demonstrated down-regulation of growth and HbF expression among erythroblasts cultured from fetal and adult human blood. The effects upon HbF were noted in a majority of cells, and quantitative PCR analysis demonstrated a transcriptional mechanism. Screening assays demonstrated that two additional molecules named 5′-deoxy adenosine and 2′,3′-dideoxy adenosine had effects on HbF comparable to SQ22536. Other adenosine derivative molecules, adenosine receptor binding ligands, and cAMP-signaling regulators failed to inhibit HbF in matched cultures. These results suggest that structurally related ribofuranose-substituted adenosine analogues act through an unknown mechanism to inhibit HbF expression in fetal and adult human erythroblasts.