title: Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome.
abstract: Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt-Hogg-Dubé syndrome-associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron-sparing. The timing of surgery is the most critical element for postoperative renal function, which is one of the important prognostic factors for Birt-Hogg-Dubé syndrome patients. The folliculin gene (FLCN) that is responsible for Birt-Hogg-Dubé syndrome was isolated as a novel tumor suppressor for kidney cancer. Recent studies using murine models for FLCN, a protein encoded by the FLCN gene, and its two binding partners, folliculin-interacting protein 1 (FNIP1) and folliculin-interacting protein 2 (FNIP2), have uncovered important roles for FLCN, FNIP1 and FNIP2 in cell metabolism, which include AMP-activated protein kinase-mediated energy sensing, Ppargc1a-driven mitochondrial oxidative phosphorylation and mTORC1-dependent cell proliferation. Birt-Hogg-Dubé syndrome is a hereditary hamartoma syndrome, which is triggered by metabolic alterations under a functional loss of FLCN/FNIP1/FNIP2 complex, a critical regulator of kidney cell proliferation rate; a mechanistic insight into the FLCN/FNIP1/FNIP2 pathway could provide us a basis for developing new therapeutics for kidney cancer.
authors.affiliation: Department of Urology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.affiliation: International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Baba
authors.affiliation: Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hasumi
authors.affiliation: Department of Molecular Pathology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Furuya
authors.affiliation: Department of Urology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
mesh_terms: D000818:Animals; D058249:Birt-Hogg-Dube Syndrome / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002352:Carrier Proteins / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009392:Nephrectomy; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C476078:FLCN protein, human; C516440:FNIP1 protein, human; C529782:FNIP2 protein, human; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Birt-Hogg-Dubé syndrome; folliculin; kidney cancer; mTORC1; mitochondria