The effect of LXR activators on AP-1 proteins in keratinocytes

J Invest Dermatol. 2004 Jul;123(1):41-8. doi: 10.1111/j.0022-202X.2004.22707.x.


Oxysterols, via activation of liver X receptor (LXR), regulate keratinocyte differentiation by stimulating transglutaminase cross-linking of several constituent proteins leading to the formation of the cornified envelope. We previously reported that oxysterols increase the expression of one of these cross-linked proteins, involucrin, and that this effect can be abolished by mutations of the distal activator protein (AP)-1 response element in the involucrin promoter. Furthermore, oxysterols increase AP-1 binding in an electrophoretic gel mobility shift assay and increase the expression of an AP-1 reporter. In this study, we describe the individual components of the AP-1 complex that are involved in the oxysterol-mediated AP-1 activation and stimulation of keratinocyte differentiation. We identified Fra-1 within the AP-1 DNA binding complex by supershift analysis of nuclear extracts from oxysterol-treated, cultured keratinocytes and confirmed that oxysterol treatment increased the levels of Fra-1 by western blot analysis. Additionally, on Western and Northern analysis, oxysterol treatment increased two other AP-1 proteins, Jun-D and c-Fos, whereas Fra-2, Jun-B, and c-Jun were not changed. Similar alterations in AP-1 proteins occurred when 25-OH-cholesterol or non-steroidal LXR agonists (GW3965, TO-901317) were used. These results indicate that oxysterols induce specific AP-1 proteins, thereby activating involucrin, one of the genes required for epidermal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cells, Cultured
  • DNA-Binding Proteins
  • Epidermal Cells
  • Gene Expression / drug effects
  • Humans
  • Hydroxycholesterols / pharmacology*
  • Keratinocytes / cytology
  • Keratinocytes / drug effects*
  • Keratinocytes / physiology
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Protein Precursors / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Transcription Factor AP-1 / metabolism*


  • DNA-Binding Proteins
  • Hydroxycholesterols
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Protein Precursors
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factor AP-1
  • fos-related antigen 1
  • 22-hydroxycholesterol
  • involucrin
  • 25-hydroxycholesterol