Digestive and Liver Disease
Volume 42, Issue 5 , Pages 377-385, May 2010

Polycystins play a key role in the modulation of cholangiocyte proliferation☆

  • Alessia Torrice

      Affiliations

    • Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy
    • ,
  • Vincenzo Cardinale

      Affiliations

    • Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy
    • ,
  • Manuela Gatto

      Affiliations

    • Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy
    • University of Rome Sapienza, Polo Pontino, Latina, Italy
    • ,
  • Rossella Semeraro

      Affiliations

    • Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy
    • University of Rome Sapienza, Polo Pontino, Latina, Italy
    • ,
  • Cristina Napoli

      Affiliations

    • Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy
    • University of Rome Sapienza, Polo Pontino, Latina, Italy
    • ,
  • Paolo Onori

      Affiliations

    • Department of Anatomy, University of Rome Sapienza, Rome, Italy
    • ,
  • Gianfranco Alpini

      Affiliations

    • Central Texas Veterans HCS, Scott & White Digestive Disease Research Center, Dept. Internal Medicine and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College Medicine, at Temple, Temple, TX 76504, United States
    • ,
  • Eugenio Gaudio

      Affiliations

    • Department of Anatomy, University of Rome Sapienza, Rome, Italy
    • ,
  • Domenico Alvaro

      Affiliations

    • Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy
    • University of Rome Sapienza, Polo Pontino, Latina, Italy
    • Corresponding Author InformationCorresponding author at: Division of Gastroenterology, Department of Clinical Medicine, University Sapienza, via R. Rossellini 51, Rome, Italy. Tel.: +39 06 49972023; fax: +39 06 4453319.

Received 24 July 2009; accepted 20 September 2009. published online 09 November 2009.

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.

Aim

We evaluated the involvement of PC-1 and PC-2 in modulating cholangiocyte proliferation.

Methods

We investigated rat cholangiocytes induced to proliferate by 17β-oestradiol. Proliferation was evaluated by PCNA immunoblotting or [3H]-thymidine incorporation into DNA. PC-1 silencing was performed by siRNA, while inhibition of regulated intramembrane proteolysis or proteasome by γ-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, γ-secretase-inhibitor and leupeptin, and the proteasome inhibitor, MG115, abolished the 17β-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.

Abbreviations: ADPKD, Autosomal Dominant Polycystic Kidney Disease, PC-1, polycystin 1, PC-2, polycystin 2, PCNA, proliferating cellular nuclear antigen, ODN, oligonucleotides, RIP, regulated intramembrane proteolysis

Keywords: Cholangiocytes, Oestradiol, Polycystic liver, Polycystins, Proliferation

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☆ Dr. Alpini was supported by the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White, the VA Research Scholar Award, and a VA Merit Award; D. Alvaro was supported by MIUR grants: PRIN #2007, prot. 2007HPT7BA_003. E. Gaudio was supported by MIUR grants: PRIN#2007, prot. 2007HPT7BA_001 and Federate Atheneaum funds from University “Sapienza” of Rome.

PII: S1590-8658(09)00394-6

doi:10.1016/j.dld.2009.09.008

Digestive and Liver Disease
Volume 42, Issue 5 , Pages 377-385, May 2010

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