Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn

Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):E1624-31. doi: 10.1073/pnas.1419502112.

Hisashi Hasumi ¹, Masaya Baba ², Yukiko Hasumi ³, Martin Lang ³, Ying Huang ³, HyoungBin F Oh ³, Masayuki Matsuo ⁴, Maria J Merino ⁵, Masahiro Yao ⁶, Yusuke Ito ⁶, Mitsuko Furuya ⁷, Yasuhiro Iribe ⁷, Tatsuhiko Kodama ⁸, Eileen Southon ⁹, Lino Tessarollo ¹⁰, Kunio Nagashima ¹¹, Diana C Haines ¹², W Marston Linehan ³, Laura S Schmidt ¹³

Affiliations

1 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Departments of Urology and Molecular Genetics and.
2 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;
3 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
4 Radiation Biology Branch and.
5 Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
6 Departments of Urology and Molecular Genetics and.
7 Molecular Pathology, Yokohama City University, Yokohama 236-0004, Japan;
8 Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan;
9 Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; and Laboratory of Animal Sciences Program.
10 Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; and.
11 Electron Microscope Laboratory, Cancer Technology Group.
12 Veterinary Pathology Section, Pathology/Histotechnology Laboratory, and.
13 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.

PMID: 25775561 DOI: 10.1073/pnas.1419502112

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.

Keywords

Birt–Hogg–Dubé syndrome; FNIP1; FNIP2; folliculin; kidney tumor.

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