Anandamide regulates keratinocyte differentiation by inducing DNA methylation in a CB1 receptor-dependent manner
Anandamide regulates keratinocyte differentiation by inducing DNA methylation in a CB1 receptor-dependent manner
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DOI：
10.1074/jbc.m707964200
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发表时间：
2008-03-07
影响因子：
4.8
通讯作者：
Maccarrone, Mauro
中科院分区：
文献类型：
--
作者：
Paradisi, Andrea;Pasquariello, Nicoletta;Maccarrone, Mauro
花生四烯醇酰胺（花生四烯醇酰胺，AEA）属于一类重要的内源性脂类，包括长链多不饱和脂肪酸的酰胺和酯类，统称为内源性大麻素。最近我们发现，AEA通过与1型大麻素受体（CB1R）结合，抑制人角质形成细胞的分化。为了进一步研究这种效应的分子机制，我们研究了AEA处理后表皮分化相关基因的表达。我们观察到角蛋白1和10，转谷氨酰胺酶5和天花苷在AEA的转录下调。最重要的是，我们发现AEA能够通过CB1R触发的分裂原激活蛋白激酶依赖通路p38和p42/44，通过增加人角化细胞的DNA甲基化来降低分化基因的表达。由于cb1r介导的甲基转移酶活性的增加，AEA对DNA甲基化的影响在这里首次被描述，我们认为这种影响的重要性显然超出了对皮肤分化的调节。事实上，内源性大麻素对DNA甲基化的调节可能会影响一些基因的表达，这些基因对这些物质的反应调节了许多细胞功能。
Anandamide ( arachidonoylethanolamide, AEA) belongs to an important class of endogenous lipids including amides and esters of long chain polyunsaturated fatty acids, collectively termed "endocannabinoids." Recently we have shown that AEA inhibits differentiation of human keratinocytes, by binding to type-1 cannabinoid receptors (CB1R). To further characterize the molecular mechanisms responsible for this effect, we investigated the expression of epidermal differentiation-related genes after AEA treatment. We observed that keratin 1 and 10, transglutaminase 5 and involucrin are transcriptionally down-regulated by AEA. Most importantly, we found that AEA is able to decrease differentiating gene expression by increasing DNA methylation in human keratinocytes, through a p38, and to a lesser extent p42/44, mitogen-activated protein kinase-dependent pathway triggered by CB1R. An effect of AEA on DNA methylation because of CB1R-mediated increase of methyltransferase activity is described here for the first time, and we believe that the importance of this effect clearly extends beyond the regulation of skin differentiation. In fact, the modulation of DNA methylation by endocannabinoids may affect the expression of a number of genes that regulate many cell functions in response to these substances.