Gene interactions and pathways from curated databases and text-mining
Hepatology 2010, PMID: 20131403

Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice.

Spirli, Carlo; Okolicsanyi, Stefano; Fiorotto, Romina; Fabris, Luca; Cadamuro, Massimiliano; Lecchi, Silvia; Tian, Xin; Somlo, Stefan; Strazzabosco, Mario

Polycystic liver disease may complicate autosomal dominant polycystic kidney disease (ADPKD), a disease caused by mutations in polycystins, which are proteins that regulate signaling, morphogenesis, and differentiation in epithelial cells. The cystic biliary epithelium [liver cystic epithelium (LCE)] secretes vascular endothelial growth factor (VEGF), which promotes liver cyst growth via autocrine and paracrine mechanisms. The expression of insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor (IGF1R), and phosphorylated mammalian target of rapamycin (p-mTOR) and the protein kinase A (PKA)-dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) are also up-regulated in LCE. We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha (HIF1alpha)-dependent VEGF secretion by IGF1 and ERK1/2. Conditional polycystin-2-knockout (Pkd2KO) mice were used for in vivo studies and to isolate cystic cholangiocytes [liver cystic epithelial cells (LCECs)]. The expression of p-mTOR, VEGF, cleaved caspase 3 (CC3), proliferating cell nuclear antigen (PCNA), IGF1, IGF1R, phosphorylated extracellular signal-regulated kinase, p-P70S6K, HIF1alpha, and VEGF in LCE, LCECs, and wild-type cholangiocytes was studied with immunohistochemistry, western blotting, or enzyme-linked immunosorbent assays. The cystic area was measured by computer-assisted morphometry of pancytokeratin-stained sections. Cell proliferation in vitro was studied with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and bromodeoxyuridine assays. The treatment of Pkd2KO mice with the mTOR inhibitor rapamycin significantly reduced the liver cyst area, liver/body weight ratio, pericystic microvascular density, and PCNA expression while increasing expression of CC3. Rapamycin inhibited IGF1-stimulated HIF1alpha accumulation and VEGF secretion in LCECs. IGF1-stimulated LCEC proliferation was inhibited by rapamycin and SU5416 (a vascular endothelial growth factor receptor 2 inhibitor). Phosphorylation of the mTOR-dependent kinase P70S6K was significantly reduced by PKA inhibitor 14-22 amide and by the mitogen signal-regulated kinase inhibitor U1026.

CONCLUSIONS

These data demonstrate that PKA-dependent up-regulation of mTOR has a central role in the proliferative, antiapoptotic, and pro-angiogenic effects of IGF1 and VEGF in polycystin-2-defective mice. This study also highlights a mechanistic link between PKA, ERK, mTOR, and HIF1alpha-mediated VEGF secretion and provides a proof of concept for the potential use of mTOR inhibitors in ADPKD and conditions with aberrant cholangiocyte proliferation.

Diseases/Pathways annotated by Medline MESH: Cysts, Disease Models, Animal, Liver Diseases, Polycystic Kidney, Autosomal Dominant
Document information provided by NCBI PubMed

Text Mining Data

extracellular signal regulated kinase 1/2 → protein kinase A (PKA): " The expression of insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor ( IGF1R ), and phosphorylated mammalian target of rapamycin ( p-mTOR ) and the protein kinase A (PKA) dependent phosphorylation of extracellular signal regulated kinase 1/2 ( ERK1/2 ) are also up-regulated in LCE "

VEGF — ERK1/2: " We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha ( HIF1alpha ) -dependent VEGF secretion by IGF1 and ERK1/2 "

VEGF — IGF1: " We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha ( HIF1alpha ) -dependent VEGF secretion by IGF1 and ERK1/2 "

VEGF → IGF1: " Rapamycin inhibited IGF1 stimulated HIF1alpha accumulation and VEGF secretion in LCECs "

HIF1alpha → IGF1: " Rapamycin inhibited IGF1 stimulated HIF1alpha accumulation and VEGF secretion in LCECs "

mTOR → PKA: " CONCLUSION : These data demonstrate that PKA dependent up-regulation of mTOR has a central role in the proliferative, antiapoptotic, and pro-angiogenic effects of IGF1 and VEGF in polycystin-2-defective mice "

VEGF → HIF1alpha: " This study also highlights a mechanistic link between PKA, ERK, mTOR, and HIF1alpha mediated VEGF secretion and provides a proof of concept for the potential use of mTOR inhibitors in ADPKD and conditions with aberrant cholangiocyte proliferation "

Manually curated Databases

No curated data.