title: Polycystin-1 promotes PKCalpha-mediated NF-kappaB activation in kidney cells.
abstract: Polycystin-1 (PC1), the PKD1 gene product, is a membrane receptor which regulates many cell functions, including cell proliferation and apoptosis, both typically increased in cyst lining cells in autosomal dominant polycystic kidney disease. Here we show that PC1 upregulates the NF-kappaB signalling pathway in kidney cells to prevent cell death. Human embryonic kidney cell lines (HEK293(CTT)), stably expressing a PC1 cytoplasmic terminal tail (CTT), presented increased NF-kappaB nuclear levels and NF-kappaB-mediated luciferase promoter activity. This, consistently, was reduced in HEK293 cells in which the endogenous PC1 was depleted by RNA interference. CTT-dependent NF-kappaB promoter activation was mediated by PKCalpha because it was blocked by its specific inhibitor Ro-320432. Furthermore, it was observed that apoptosis, which was increased in PC1-depleted cells, was reduced in HEK293(CTT) cells and in porcine kidney LtTA cells expressing a doxycycline-regulated CTT. Staurosporine, a PKC inhibitor, and parthenolide, a NF-kappaB inhibitor, significantly reduced the CTT-dependent antiapoptotic effect. These data reveal, therefore, a novel pathway by which polycystin-1 activates a PKCalpha-mediated NF-kappaB signalling and cell survival.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Banzi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Aguiari
authors.forename: Viky
authors.initials: V
authors.lastname: Trimi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangolini
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.forename: Ralph
authors.initials: R
authors.lastname: Witzgall
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.forename: Laura
authors.initials: L
authors.lastname: del Senno
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D034622:RNA Interference; D050396:TRPP Cation Channels / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D016328:NF-kappa B; D051571:Protein Kinase C-alpha; D050396:TRPP Cation Channels