Department of Biochemistry and Molecular Biology, the University of Texas-Houston Medical School, Houston, Texas, USA.
Drug Metab Dispos. 2010 Jan;38(1):100-7. doi: 10.1124/dmd.109.029025.
Mechanisms regulating CYP4F genes remain under investigation, although characterization of CYP4F regulatory modalities would facilitate the discovery of new drug targets. This present study shows that all-trans- and 9-cis-retinoic acids can inhibit CYP4F11 expression in human keratinocyte-derived HaCaT cells. Transrepression of many genes by retinoic acids is mediated by interactions between retinoid receptors and the activator protein 1 (AP-1) complex. Proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta, which can activate the AP-1 complex, induce CYP4F11 transcription in HaCaT cells. The c-Jun N-terminal kinase (JNK)-specific inhibitor 1,9-pyrazoloanthrone (SP600125) blocked the induction of CYP4F11 by both cytokines, indicating involvement of the JNK pathway. Furthermore, TNF-alpha failed to induce CYP4F11 transcription when HaCaT cells were preincubated with retinoic acids. Retinoic acids are ligands for the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RXR agonist 6-(1(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl) nicotinic acid (LG268) greatly induced CYP4F11 transcription, whereas the RAR agonist 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TTNPB) markedly inhibited CYP4F11 transcription, indicating that down-regulation of CYP4F11 transcription by retinoic acid is mediated by RARs and may also be related to ligand competition for RXRs. Thus, the CYP4F11 gene is positively regulated by multiple signaling pathways in HaCaT keratinocytes, including RXR and JNK signaling pathways.
调控 CYP4F 基因的机制仍在研究中，尽管对 CYP4F 调控方式的特征描述将有助于发现新的药物靶点。本研究表明，全反式和 9-顺式视黄酸可以抑制人角质形成细胞来源的 HaCaT 细胞中 CYP4F11 的表达。视黄酸通过视黄酸受体与激活蛋白 1（AP-1）复合物之间的相互作用来转录抑制许多基因。促炎细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素 1β（IL-1β）可激活 AP-1 复合物，诱导 HaCaT 细胞中 CYP4F11 的转录。c-Jun N-末端激酶（JNK）特异性抑制剂 1,9-吡唑并蒽酮（SP600125）阻断了两种细胞因子诱导的 CYP4F11 的诱导，表明 JNK 途径的参与。此外，当 HaCaT 细胞用视黄酸预孵育时，TNF-α未能诱导 CYP4F11 转录。视黄酸是视黄酸受体（RARs）和视黄醇 X 受体（RXRs）的配体。RXR 激动剂 6-（1（3,5,5,8,8-五甲基-5,6,7,8-四氢萘-2-基）环丙基）烟酰胺（LG268）极大地诱导 CYP4F11 转录，而 RAR 激动剂 4-（2-（5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基）-1-丙烯基）苯甲酸（TTNPB）显著抑制 CYP4F11 转录，表明视黄酸下调 CYP4F11 转录是由 RAR 介导的，也可能与 RXR 的配体竞争有关。因此，CYP4F11 基因在 HaCaT 角质形成细胞中受多种信号通路的正调控，包括 RXR 和 JNK 信号通路。
