Retinoid-dependent transcriptional suppression of cytokeratin gene expression in human epidermal squamous cell carcinoma cells.
Retinoid-dependent transcriptional suppression of cytokeratin gene expression in human epidermal squamous cell carcinoma cells.
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人表皮鳞状细胞癌细胞中细胞角蛋白基因表达的视黄醇依赖性转录抑制。
DOI：
10.1111/j.1432-0436.1993.tb00629.x
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Eckert,RL
中科院分区：
文献类型：
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作者：
Agarwal,C;Rorke,EA;Boyce,M;Howard,J;Crish,J;Hufeisen,S;Eckert,RL
我们以前已经证明，细胞角蛋白水平协调调节正常培养的人角质形成细胞。在本研究中，我们使用人类鳞状细胞癌（SCC）细胞研究这种调节的机制。用20或200 nM反式维甲酸处理SCC-13细胞导致细胞角蛋白K5和K6表达几乎完全抑制。这种变化伴随着编码K5和K6的mRNA水平的同时降低（> 20倍）。转录分析表明，K5和K6基因的转录速率下降了约4至5倍，在类维生素A处理的细胞核。视黄醇（2000 nM）也促进了这种变化。相反，细胞角蛋白K19在维甲酸存在下不增加，因此类维生素A对角蛋白基因表达的正常协调调节在SCC-13细胞中似乎是解偶联的。然而，这并不代表类维生素A对基因表达的正调控的一般缺陷，因为在瞬时转染测定中，反式视黄酸正调控含有来自视黄酸受体β基因的类维生素A反应元件的报告质粒。（乙酯）及其代谢衍生物Ro 13-7410（游离酸）在调节正常角质形成细胞的分化中均具有活性。相比之下，只有Ro 13-7410在SCC-13细胞中具有活性。由于Ro 13-6298与视黄酸受体结合不良，这表明SCC-13细胞与正常角质形成细胞不同，缺乏将Ro 13-6298转化为活性Ro 13-7410的能力。这些结果进一步表明，不能代谢类维生素A乙酯可能是转化的表皮角质形成细胞的特性。
We have previously demonstrated that cytokeratin levels are coordinately regulated in normal cultured human keratinocytes. In the present study we examine the mechanism of this regulation using human squamous cell carcinoma (SCC) cells. Treatment of SCC‐13 cells with 20 or 200 nMtrans‐retinoic acid results in nearly complete suppression of cytokeratin K5 and K6 expression. This change is accompanied by a simultaneous reduction (> 20‐fold) in the level of the mRNAs encoding K5 and K6. Transcriptional analysis indicates that the transcription rate of the K5 and K6 genes drops by approximately four to fivefold in retinoid treated nuclei. Retinol (2000 nM) also promotes this change. In contrast, cytokeratin K19 does not increase in the presence of retinoic acid, thus the normal coordinate regulation of keratin gene expression by retinoids appears to be uncoupled in SCC‐13 cells. However, this does not represent a general defect in positive regulation of gene expression by retinoids, since in a transient transfection assay trans‐retinoic acid positively regulates a reporter plasmid containing the retinoid response element from the retinoic acid receptor‐β gene.The synthetic retinoids Ro 13–6298 (ethyl ester) and its metabolic derivative Ro 13–7410 (free acid) are both active in modulating the differentiation of normal keratinocytes. In contrast, only Ro 13–7410 is active in SCC‐13 cells. As Ro 13–6298 binds poorly to the retinoic acid receptors, this suggests that SCC‐13 cells, unlike normal keratinocytes, lack the ability to convert Ro 13–6298 to the active Ro 13–7410. These results further suggest that an inability to metabolize retinoid ethyl esters may be a property of transformed epidermal keratinocytes.