Gene regulation of CYP4F11 in human keratinocyte HaCaT cells

Drug Metab Dispos. 2010 Jan;38(1):100-7. doi: 10.1124/dmd.109.029025.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alitretinoin
  • Anthracenes / pharmacology
  • Benzoates / pharmacology
  • Cell Line
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P450 Family 4
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Humans
  • Interleukin-1alpha / pharmacology
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Nicotinic Acids / pharmacology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Retinoic Acid / agonists
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptor alpha / agonists
  • Retinoid X Receptor alpha / genetics
  • Retinoid X Receptor alpha / metabolism
  • Retinoid X Receptor beta / agonists
  • Retinoid X Receptor beta / genetics
  • Retinoid X Receptor beta / metabolism
  • Retinoids / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tetrahydronaphthalenes / pharmacology
  • Tretinoin / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Anthracenes
  • Benzoates
  • Interleukin-1alpha
  • Nicotinic Acids
  • Protein Kinase Inhibitors
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptor alpha
  • Retinoid X Receptor beta
  • Retinoids
  • Tetrahydronaphthalenes
  • Tumor Necrosis Factor-alpha
  • retinoic acid receptor gamma
  • pyrazolanthrone
  • Alitretinoin
  • Tretinoin
  • 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid
  • Cytochrome P-450 Enzyme System
  • Cytochrome P450 Family 4
  • CYP4F11 protein, human
  • JNK Mitogen-Activated Protein Kinases
  • LG 100268