title: Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia.
abstract: The Birt-Hogg-Dubé (BHD) disease is a genetic cancer syndrome. The responsible gene, BHD, has been identified by positional cloning and thought to be a novel tumor suppressor gene. BHD mutations cause many types of diseases including renal cell carcinomas, fibrofolliculomas, spontaneous pneumothorax, lung cysts, and colonic polyps/cancers. By combining Gateway Technology with the Ksp-Cre gene knockout system, we have developed a kidney-specific BHD knockout mouse model. BHD(flox/flox)/Ksp-Cre mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. The affected BHD(flox/flox)/Ksp-Cre mice died of renal failure at approximate three weeks of age, having blood urea nitrogen levels over tenfold higher than those of BHD (flox/+)/Ksp-Cre and wild-type littermate controls. We further demonstrated that these phenotypes were caused by inactivation of BHD and subsequent activation of the mTOR pathway. Application of rapamycin, which inhibits mTOR activity, to the affected mice led to extended survival and inhibited further progression of cystogenesis. These results provide a correlation of kidney-targeted gene inactivation with renal carcinoma, and they suggest that the BHD product FLCN, functioning as a cyst and tumor suppressor, like other hamartoma syndrome-related proteins such as PTEN, LKB1, and TSC1/2, is a component of the mTOR pathway, constituting a novel FLCN-mTOR signaling branch that regulates cell growth/proliferation.
authors.affiliation: Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Jindong
authors.initials: J
authors.lastname: Chen
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Futami
authors.forename: David
authors.initials: D
authors.lastname: Petillo
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wang
authors.forename: Jared
authors.initials: J
authors.lastname: Knol
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Sok-Kean
authors.initials: SK
authors.lastname: Khoo
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Karl
authors.initials: K
authors.lastname: Dykema
authors.forename: Karl
authors.initials: K
authors.lastname: Dykyma
authors.forename: Racheal
authors.initials: R
authors.lastname: Zhang
authors.forename: Brian
authors.initials: B
authors.lastname: Cao
authors.forename: Ximing J
authors.initials: XJ
authors.lastname: Yang
authors.forename: Kyle
authors.initials: K
authors.lastname: Furge
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D003001:Cloning, Molecular; D004622:Embryo, Mammalian; D005804:Genes, Lethal; D016147:Genes, Tumor Suppressor / Q000502:physiology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009928:Organ Specificity / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases