title: Polycystins play a key role in the modulation of cholangiocyte proliferation.
abstract: BACKGROUND
  Polycystin-1 and -2 (PC-1 and PC-2) are critical components of primary cilia, which act as mechanosensors and drive cell response to injury. PC-1 activation involves the cleavage/processing of PC-1 cytoplasmic tail, driven by regulated intramembrane proteolysis or ubiquitine/proteasome, translocation in the nucleus and activation of transcription factors. Mutations of PC-1 or PC-2 occur in polycystic liver where cholangiocyte proliferation is enhanced.
  
  
  OBJECTIVE
  We evaluated the involvement of PC-1 and PC-2 in modulating cholangiocyte proliferation.
  
  
  METHODS
  We investigated rat cholangiocytes induced to proliferate by 17beta-oestradiol. Proliferation was evaluated by PCNA immunoblotting or [(3)H]-thymidine incorporation into DNA. PC-1 silencing was performed by siRNA, while inhibition of regulated intramembrane proteolysis or proteasome by gamma-secretase inhibitor, leupeptin or MG115.
  
  
  RESULTS
  Cholangiocyte proliferation was associated with decreased PC-1 and PC-2 expression, which was inversely correlated with enhanced PCNA. The selective silencing of PC-1 induced activation of cholangiocyte proliferation in association with decreased PC-1 expression. Two different regulated intramembrane proteolysis inhibitors, gamma-secretase-inhibitor and leupeptin, and the proteasome inhibitor, MG115, abolished the 17beta-oestradiol proliferative effect.
  
  
  CONCLUSIONS
  PC-1 and PC-2 play a major role as modulators of cholangiocyte proliferation suggesting that primary cilia may act as sensors of cell injury driving, when activated, a proliferative cholangiocyte response to trigger the reparative processes.
authors.affiliation: Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Torrice
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cardinale
authors.forename: Manuela
authors.initials: M
authors.lastname: Gatto
authors.forename: Rossella
authors.initials: R
authors.lastname: Semeraro
authors.forename: Cristina
authors.initials: C
authors.lastname: Napoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000166:cytology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D050396:TRPP Cation Channels / Q000502:physiology*
chemical_list: D050396:TRPP Cation Channels