title: Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn.
abstract: Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys. We found that absolute Fnip2 mRNA copy number was low relative to Fnip1 in organs that showed phenotypes under Fnip1 deficiency but was comparable to Fnip1 mRNA copy number in mouse kidney. Strikingly, kidney-targeted Fnip1/Fnip2 double inactivation produced enlarged polycystic kidneys, as was previously reported in Flcn-deficient kidneys. Kidney-specific Flcn inactivation did not further augment kidney size or cystic histology of Fnip1/Fnip2 double-deficient kidneys, suggesting pathways dysregulated in Flcn-deficient kidneys and Fnip1/Fnip2 double-deficient kidneys are convergent. Heterozygous Fnip1/homozygous Fnip2 double-knockout mice developed kidney cancer at 24 mo of age, analogous to the heterozygous Flcn knockout mouse model, further supporting the concept that Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn and that kidney tumorigenesis in human Birt-Hogg-Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Our findings uncover important roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Departments of Urology and Molecular Genetics and.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; International Research Center for Medical Sciences, Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 860-0811, Japan;
authors.forename: Masaya
authors.initials: M
authors.lastname: Baba
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hasumi
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Martin
authors.initials: M
authors.lastname: Lang
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: HyoungBin F
authors.initials: HF
authors.lastname: Oh
authors.affiliation: Radiation Biology Branch and.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.affiliation: Departments of Urology and Molecular Genetics and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
authors.affiliation: Departments of Urology and Molecular Genetics and.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Molecular Pathology, Yokohama City University, Yokohama 236-0004, Japan;
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Furuya
authors.affiliation: Molecular Pathology, Yokohama City University, Yokohama 236-0004, Japan;
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Iribe
authors.affiliation: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan;
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; and Laboratory of Animal Sciences Program.
authors.forename: Eileen
authors.initials: E
authors.lastname: Southon
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; and.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Electron Microscope Laboratory, Cancer Technology Group.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Veterinary Pathology Section, Pathology/Histotechnology Laboratory, and.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Haines
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702 schmidtl@mail.nih.gov.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
mesh_terms: D000483:Alleles; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D058249:Birt-Hogg-Dube Syndrome / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C526060:Bhd protein, mouse; D002352:Carrier Proteins; C581709:FNIP1 protein, mouse; C574800:MAPO1 protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins
keywords: Birt–Hogg–Dubé syndrome; FNIP1; FNIP2; folliculin; kidney tumor