GAR22: A novel target gene of thyroid hormone receptor causes growth inhibition in human erythroid cells
GAR22: A novel target gene of thyroid hormone receptor causes growth inhibition in human erythroid cells
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DOI：
10.1016/j.exphem.2009.02.002
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发表时间：
2009-05-01
影响因子：
2.6
通讯作者：
Zenke, Martin
中科院分区：
文献类型：
--
作者：
Gamper, Ivonne;Koh, Ki-Ryang;Zenke, Martin
Objective.甲状腺激素受体（TR）是配体依赖性转录因子，对红系细胞发育有重要影响。在这里，我们研究了TR对红细胞基因表达的活性，并确定了TR靶基因。确定TR靶基因GAR 22（22号染色体上的生长停滞特异性2 [GAS 2]相关基因）对红细胞分化的影响。干细胞因子/促红细胞生成素（SCF/EPO）依赖的红细胞祖细胞在体外分化的存在或不存在的甲状腺激素。激素诱导的基因表达的变化是通过DNA微阵列的全基因组方法来测量的。TR靶基因GAR 22的异位表达被用于确定其对红细胞分化的影响。配体激活的TR在体外有效地加速红细胞祖细胞分化，同时诱导生长停滞。我们证明，激活TR诱导的特定基因表达模式的上调或下调的基因，包括不同的集群与加速分化的治疗反应。对T3诱导基因的挖掘确定了基础转录元件结合蛋白1/Kruppel样因子9（BTEB 1/KLF 9）和GAR 22为TR靶基因。BTEB 1/KLF 9是已知的TR靶基因，而GAR 22最初被鉴定为推定的肿瘤抑制基因，代表新的TR靶基因。我们证明了GAR 22在红细胞祖细胞中的异位表达延长了细胞周期并导致生长抑制，但红细胞基因表达不受影响。本研究将GAR 22确定为一个新的直接TR靶基因。我们的研究结果表明，甲状腺素诱导的GAR 22可能是甲状腺激素诱导的红细胞祖细胞生长抑制的重要触发因素。(c)2009 ISEH -血液学和干细胞学会。爱思唯尔公司出版
Objective. Thyroid hormone receptors (TRs) are ligand-dependent transcription factors with a major impact on erythroid cell development. Here we investigated TR activity on red cell gene expression and identified TR target genes. The impact of the TR target gene GAR22 (growth arrest-specific 2 [GAS2]-related gene on chromosome 22) on red cell differentiation was determined.Materials and Methods. Stem cell factor/erythropoietin (SCF/EPO)-dependent red cell progenitors were differentiated in vitro in the presence or absence of thyroid hormone. Hormone-induced changes in gene expression were measured by a genome-wide approach with DNA microarrays. Ectopic expression of the TR target gene GAR22 was used to determine its impact on red cell differentiation.Results. Ligand-activated TR effectively accelerated red cell progenitor differentiation in vitro concomitantly with inducing growth arrest. We demonstrate that activated TR-induced specific gene expression patterns of up- or downregulated genes, including distinct clusters associated with accelerated differentiation in response to treatment. Mining for T3-induced genes identified basic transcription element binding protein 1/Kruppel-like factor 9 (BTEB1/KLF9) and GAR22 as TR target genes. BTEB1/KLF9 is a known TR target gene while GAR22, initially identified as a putative tumor suppressor, represents a novel TR target gene. We demonstrate that ectopic GAR22 expression in red cell progenitors lengthens the cell cycle and causes growth inhibition, but leaves red cell gene expression unaffected.Conclusion. This study identifies GAR22 as a novel and direct TR target gene. Our results suggest that hormone-induced GAR22 might represent an important trigger of growth inhibition induced by thyroid hormone in red cell progenitors. (c) 2009 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.