title: Differential and bi-directional regulation between TR2/TR4 orphan nuclear receptors and a specific ligand mediated-peroxisome proliferator-activated receptor alpha in human HaCaT keratinocytes.
abstract: BACKGROUND
  We have reported that human TR2 orphan nuclear receptor (TR2) can modulate the transcriptional activity of the reporter gene containing an AGGTCA direct repeat-hormone response element.
  
  
  OBJECTIVE
  The aim of this study is to investigate the potential role and regulation of TR2 in human HaCaT keratinocytes.
  
  
  METHODS
  We performed mainly chloramphenicol acetyltransferase reporter gene assays (CAT assays), and Western blot analysis.
  
  
  RESULTS
  From CAT assays, TR2 can suppress retinoic acid (RA)-induced transactivation by 44.7% in HaCaT keratinocytes. This suppression is similar to our previous report showing TR4 orphan nuclear receptor (TR4) can suppress RA-induced transactivation. However, TR4 but not TR2 can significantly repress Wy-14643-mediated peroxisome proliferator-activated receptor alpha (PPAR alpha) transactivation by 95%. Western blot analysis suggested that Wy-14643 can differentially regulate the expression of TR2 and TR4 (by increasing the expression of TR4 protein and decreasing that of TR2) in HaCaT keratinocytes.
  
  
  CONCLUSIONS
  Our data not only provides the first evidence to demonstrate that close members of orphan nuclear receptors group, such as TR2 and TR4, can have distinct functions, but also suggests the existence of differential and bi-directional regulation between PPAR alpha and TR2/TR4, that may play some important roles in the PPAR alpha signaling pathway in human keratinocytes.
authors.affiliation: Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Inui
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lee
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.forename: Chih-Rong
authors.initials: CR
authors.lastname: Shyr
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008024:Ligands; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism* / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000378:metabolism* / Q000502:physiology; D020218:Response Elements / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D008024:Ligands; C539822:NR2C1 protein, human; C490515:NR2C2 protein, human; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D014212:Tretinoin; C006253:pirinixic acid