title: Cyclosporine A enhances gingival β-catenin stability via Wnt signaling.
abstract: BACKGROUND
  Cyclosporine A (CsA) increases β-catenin messenger RNA (mRNA) and protein expression. The present study demonstrates that Wnt/β-catenin signaling inhibits β-catenin degradation in the gingiva.
  
  
  METHODS
  Forty 5-week-old male Sprague-Dawley rats were assigned to two study groups after healing from right maxillary molar extractions. The rats in the experimental group were fed 30 mg/kg CsA daily for 4 weeks, whereas the control rats were fed mineral oil. At the end of the study, all rats were sacrificed, and the gingivae were obtained. The gingival morphology after CsA treatment was evaluated by histology, and the genes related to Wnt/β-catenin signaling were initially screened by microarray. Polymerase chain reaction, Western blotting, and immunohistochemistry were used to examine the mRNA and protein expression of proliferating cell nuclear antigen, cyclin D1, E-cadherin, β-catenin, Dvl-1, glycogen synthase kinase-3β, axin-1, and adenomatous polyposis coli (APC). Phosphoserine and ubiquitinylated β-catenin were detected after immunoprecipitation.
  
  
  RESULTS
  In rats treated with CsA, overgrowth of gingivae was observed, and altered expression of genes related to Wnt/β-catenin signaling was detected by the microarray. The gingival mRNA and protein expression profiles for genes associated with Wnt/β-catenin signaling further confirmed the effect of CsA: β-catenin and Dvl-1 expression increased, but APC and axin-1 expression decreased. Western blotting and immunohistochemistry showed decreases in β-catenin serine phosphorylation (33/37) and ubiquitinylation in the gingivae of CsA-treated rats.
  
  
  CONCLUSIONS
  CsA-enhanced gingival β-catenin stability may be involved in gene upregulation or β-catenin degradation via the Wnt/β-catenin pathway.
authors.affiliation: Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, ROC.
authors.forename: Hsiao-Pei
authors.initials: HP
authors.lastname: Tu
authors.forename: Yen-Teen
authors.initials: YT
authors.lastname: Chen
authors.forename: Earl
authors.initials: E
authors.lastname: Fu
authors.forename: E-Chin
authors.initials: EC
authors.lastname: Shen
authors.forename: Meng-Hsun
authors.initials: MH
authors.lastname: Wu
authors.forename: Yen-Lin
authors.initials: YL
authors.lastname: Chen
authors.forename: Cheng-Yang
authors.initials: CY
authors.lastname: Chiang
authors.forename: Hsien-Chung
authors.initials: HC
authors.lastname: Chiu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects; D025601:Adenomatous Polyposis Coli Protein / Q000187:drug effects; D000818:Animals; D060466:Axin Protein / Q000187:drug effects; D015820:Cadherins / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D000072261:Dishevelled Proteins; D005881:Gingiva / Q000187:drug effects*; D019214:Gingival Overgrowth / Q000139:chemically induced / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D010750:Phosphoproteins / Q000187:drug effects; D010768:Phosphoserine / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C555453:Axin1 protein, rat; D015820:Cadherins; C530106:Ccnd1 protein, rat; C495268:Ctnnb1 protein, rat; D000072261:Dishevelled Proteins; C000606580:Dvl1 protein, rat; D007166:Immunosuppressive Agents; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D051176:beta Catenin; D019938:Cyclin D1; D010768:Phosphoserine; D016572:Cyclosporine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: Anti-inflammatory agents; Wnt signaling pathway; beta catenin; cyclosporine; gingival hyperplasia; phosphorylation