PT  - JOURNAL ARTICLE
AU  - Ying Wang
AU  - Jordan C. Bell
AU  - Diane S. Keeney
AU  - Henry W. Strobel
TI  - Gene Regulation of <em>CYP4F11</em> in Human Keratinocyte HaCaT Cells
AID  - 10.1124/dmd.109.029025
DP  - 2010 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 100--107
VI  - 38
IP  - 1
4099  - http://dmd.aspetjournals.org/content/38/1/100.short
4100  - http://dmd.aspetjournals.org/content/38/1/100.full
SO  - Drug Metab Dispos2010 Jan 01; 38
AB  - 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 α (TNF-α) and interleukin 1β, 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-α 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics