title: Cyclooxygenase-2 inhibition restores ultraviolet B-induced downregulation of ATP2A2/SERCA2 in keratinocytes: possible therapeutic approach of cyclooxygenase-2 inhibition for treatment of Darier disease.
abstract: BACKGROUND
  ATP2A2 encoding the sarcoplasmic/endoplasmic reticulum Ca(2+) -ATPase2 (SERCA2) is a Darier disease (DD)-related gene. Ultraviolet (UV) B irradiation downregulates ATP2A2/SERCA2 expression in keratinocytes, whereas cyclooxygenase-2 (COX-2) expression is dramatically upregulated by UVB.
  
  
  OBJECTIVE
  To analyse the involvement of COX-2 in ATP2A2/SERCA2 expression.
  
  
  METHODS
  Keratinocytes were transfected with COX-2 siRNA or treated with COX-2 inhibitor, celecoxib, to evaluate the effect of COX-2 on ATP2A2/SERCA2 expression. Quantitative real-time polymerase chain reaction, Western blotting analysis and reporter assay were used to determine the amount of mRNA, protein level and transcription activity, respectively.
  
  
  RESULTS
  COX-2 knockdown by siRNA resulted in upregulation of ATP2A2 transcription. Treatment by celecoxib rescued UVB-mediated suppression of the ATP2A2 transcription and SERCA2 protein expression. Simple addition of prostaglandin (PG) E(2) , which is a product of COX-2 enzyme, reduced the amounts of ATP2A2 mRNA and SERCA2 protein in keratinocytes.
  
  
  CONCLUSIONS
  UVB downregulates ATP2A2/SERCA2 expression via induction of COX-2 expression and subsequent increase of PGE(2) production in keratinocytes. Considering that DD is caused by the decreased function of SERCA2 due to the reduced expression of the ATP2A2 gene, this finding shows the possibility that COX-2 inhibition may be useful to prevent and/or treat DD.
authors.affiliation: Department of Dermatology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kamijo
authors.forename: C
authors.initials: C
authors.lastname: Nishiyama
authors.forename: A
authors.initials: A
authors.lastname: Takagi
authors.forename: N
authors.initials: N
authors.lastname: Nakano
authors.forename: M
authors.initials: M
authors.lastname: Hara
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: H
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D007644:Darier Disease / Q000628:therapy*; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D015232:Dinoprostone