Polycystins play a key role in the modulation of cholangiocyte proliferation.
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.
Torrice
Alessia
A
Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy.
Cardinale
Vincenzo
V
Gatto
Manuela
M
Semeraro
Rossella
R
Napoli
Cristina
C
Onori
Paolo
P
Alpini
Gianfranco
G
Gaudio
Eugenio
E
Alvaro
Domenico
D
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*
D050396:TRPP Cation Channels