Retinoid-responsive transcriptional changes in epidermal keratinocytes.
Retinoid-responsive transcriptional changes in epidermal keratinocytes.
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DOI：
10.1002/jcp.21784
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发表时间：
2009-08
影响因子：
5.6
通讯作者：
Tomic-Canic, Marjana
中科院分区：
文献类型：
--
作者：
Lee, Ding-Dar;Stojadinovic, Olivera;Krzyzanowska, Agata;Vouthounis, Constantinos;Blumenberg, Miroslav;Tomic-Canic, Marjana
类维生素A（RA）已被用作许多皮肤疾病的治疗剂，从牛皮癣到痤疮和皱纹。虽然已知RA抑制角质形成细胞分化，但RA在表皮中的分子效应尚未全面定义。为了确定RA在原代人表皮角质形成细胞中的转录靶点，我们使用大型DNA微阵列比较了在全反式维甲酸存在或不存在下生长1、4、24、48和72小时的细胞的转录谱。正如预期的那样，RA抑制角化的蛋白质标志物;然而，负责表皮脂质、长链脂肪酸、胆固醇和鞘脂的生物合成的基因也被抑制。重要的是，RA的合成、酯化和代谢途径被RA激活;因此，RA调节其自身的生物利用度。出乎意料的是，RA调节许多与细胞周期和程序性细胞死亡相关的基因。这使我们揭示了RA对角质形成细胞增殖和凋亡的新作用。对RA的反应非常快：315个基因在1小时后已经被调节。超过三分之一的RA调控基因在信号转导和转录调控中发挥作用。使用计算机分析，我们确定了一组过度代表的RA调控基因的转录因子结合位点。许多银屑病相关基因受到RA的调控，有些被诱导，有些被抑制。这些结果全面记录了RA在角质形成细胞中引起的转录变化，为RA在表皮中影响的分子机制提供了新的见解，并证明了DNA微阵列分析的假设生成能力。
Retinoids (RA) have been used as therapeutic agents for numerous skin diseases, from psoriasis to acne and wrinkles. While RA is known to inhibit keratinocyte differentiation, the molecular effects of RA in epidermis have not been comprehensively defined. To identify the transcriptional targets of RA in primary human epidermal keratinocytes, we compared the transcriptional profiles of cells grown in the presence or absence of all-trans retinoic acid for 1, 4, 24, 48 and 72 hours, using large DNA microarrays. As expected, RA suppresses the protein markers of cornification; however the genes responsible for biosynthesis of epidermal lipids, long-chain fatty acids, cholesterol, and sphingolipids, are also suppressed. Importantly, the pathways of RA synthesis, esterification and metabolism are activated by RA; therefore, RA regulates its own bioavailability. Unexpectedly, RA regulates many genes associated with the cell cycle and programmed cell death. This led us to reveal novel effects of RA on keratinocyte proliferation and apoptosis. The response to RA is very fast: 315 genes were regulated already after 1 h. More than one-third of RA-regulated genes function in signal transduction and regulation of transcription. Using in silico analysis, we identified a set of over-represented transcription factor binding sites in the RA-regulated genes. Many psoriasis-related genes are regulated by RA, some induced, others suppressed. These results comprehensively document the transcriptional changes caused by RA in keratinocytes, add new insights into the molecular mechanism influenced by RA in the epidermis and demonstrate the hypothesis-generating power of DNA microarray analysis.
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DOI：
10.1091/mbc.1.11.791
发表时间：
1990-10-01
期刊：
CELL REGULATION
影响因子：
--
作者：
CHOI, Y;FUCHS, E
通讯作者：
FUCHS, E
影响因子：
4.6
作者：
Boucherat, Olivier;Franco-Montoya, Marie-Laure;Bourbon, Jacques R.
通讯作者：
Bourbon, Jacques R.
影响因子：
5.3
作者：
FLOYD, EE;JETTEN, AM
通讯作者：
JETTEN, AM
影响因子：
3.6
作者：
Bernard, FX;Pedretti, N;Deguercy, A
通讯作者：
Deguercy, A
影响因子：
6.5
作者：
Gazel, A;Ramphal, P;Blumenberg, M
通讯作者：
Blumenberg, M