title: Human folliculin delays cell cycle progression through late S and G2/M-phases: effect of phosphorylation and tumor associated mutations.
abstract: The Birt-Hogg-Dube disease occurs as a result of germline mutations in the human Folliculin gene (FLCN), and is characterized by clinical features including fibrofolliculomas, lung cysts and multifocal renal neoplasia. Clinical and genetic evidence suggest that FLCN acts as a tumor suppressor gene. The human cell line UOK257, derived from the renal cell carcinoma of a patient with a germline mutation in the FLCN gene, harbors a truncated version of the FLCN protein. Reconstitution of the wild type FLCN protein into UOK257 cells delays cell cycle progression, due to a slower progression through the late S and G2/M-phases. Similarly, Flcn (-/-) mouse embryonic fibroblasts progress more rapidly through the cell cycle than wild type controls (Flcn (flox/flox)). The reintroduction of tumor-associated FLCN mutants (FLCN ΔF157, FLCN 1-469 or FLCN K508R) fails to delay cell cycle progression in UOK257 cells. Additionally, FLCN phosphorylation (on Serines 62 and 73) fluctuates throughout the cell cycle and peaks during the G2/M phase in cells treated with nocodazole. In keeping with this observation, the reintroduction of a FLCN phosphomimetic mutant into the UOK257 cell line results in faster progression through the cell cycle compared to those expressing the wild type FLCN protein. These findings suggest that the tumor suppression function of FLCN may be linked to its impact on the cell cycle and that FLCN phosphorylation is important for this activity. Additionally, these observations describe a novel in vitro assay for testing the functional significance of FLCN mutations and/or genetic polymorphisms.
authors.affiliation: Center for Cancer Research at The Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, United States of America.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Laviolette
authors.forename: Jonas
authors.initials: J
authors.lastname: Wilson
authors.forename: Julia
authors.initials: J
authors.lastname: Koller
authors.forename: Christopher
authors.initials: C
authors.lastname: Neil
authors.forename: Peter
authors.initials: P
authors.lastname: Hulick
authors.forename: Tomas
authors.initials: T
authors.lastname: Rejtar
authors.forename: Barry
authors.initials: B
authors.lastname: Karger
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.forename: Othon
authors.initials: O
authors.lastname: Iliopoulos
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000235:genetics*; D045744:Cell Line, Tumor; D004970:Estrone / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D016195:G2 Phase / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins; D004970:Estrone