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

Authors:
Hisashi Hasumi
Hisashi Hasumi
Yokohama City University Graduate School of Medicine
Japan
Masaya Baba
Masaya Baba
National Cancer Institute
United States
Yukiko Hasumi
Yukiko Hasumi
National Cancer Institute
United States
Martin Lang
Martin Lang
Università di Bologna
Italy
Ying Huang
Ying Huang
Fred Hutchinson Cancer Research Center
Seattle | United States
Hyoungbin F Oh
Hyoungbin F Oh
National Institutes of Health (NIH)
United States
Masayuki Matsuo
Masayuki Matsuo
Gifu University School of Medicine
Maria J Merino
Maria J Merino
Laboratory of Pathology
United States

Proc Natl Acad Sci U S A 2015 Mar 16;112(13):E1624-31. Epub 2015 Mar 16.

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

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.
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http://dx.doi.org/10.1073/pnas.1419502112DOI ListingPossible
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386336PMCFound
March 2015
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