Journal Article

Renal tumour suppressor function of the Birt–Hogg–Dubé syndrome gene product folliculin

Crosby, K, Pause, A, Kottis, V, Uetani, N, Paquet, M, Pomerleau, V, Ghazi, A, Sabourin, S, Hudon, V, Dydensborg, A B

2010

Overview

BackgroundRenal cell carcinoma (RCC) comprises five major molecular and histological subtypes. The Birt–Hogg–Dubé (BHD) syndrome is a hereditary human cancer syndrome that predisposes affected individuals to develop renal carcinoma of nearly all subtypes, in addition to benign fibrofolliculomas, and pulmonary and renal cysts. BHD is caused by loss-of-function mutations in the folliculin (FLCN) protein. The molecular function of FLCN is still largely unknown; opposite and conflicting evidence of the role of FLCN in mammalian target of rapamycin signalling/phosphorylated ribosomal protein S6 (p-S6) activation had recently been reported.Results and MethodsHere, the expression pattern of murine Flcn was described, and it was observed that homozygous disruption of Flcn results in embryonic lethality early during development. Importantly, heterozygous animals manifest early preneoplastic kidney lesions, devoid of Flcn expression, that progress towards malignancy, including cystopapillary adenomas. A bona fide tumour suppressor activity of FLCN was confirmed by nude mouse xenograft assays of two human RCC cell lines with either diminished or re-expressed FLCN. It was observed that loss of FLCN expression leads to context-dependent effects on S6 activation. Indeed, solid tumours and normal kidneys show decreased p-S6 upon diminished FLCN expression. Conversely, p-S6 is found to be elevated or absent in FLCN-negative renal cysts.ConclusionIn accordance with clinical data showing distinct renal malignancies arising in BHD patients, in this study FLCN is shown as a general tumour suppressor in the kidney.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group,BMJ Publishing Group LTD
• Subject: Animals / BHD / BHD syndrome / Biological and medical sciences / Birt–Hogg–Dubé / cancer: urological / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - pathology / cell biology / Cell Proliferation / Cysts / Disease Models, Animal / embryonic day / FLCN / folliculin / Fundamental and applied biological sciences. Psychology / Gene Expression Regulation, Neoplastic / General aspects. Genetic counseling / Genes, Tumor Suppressor - physiology / Genetic Predisposition to Disease / Genetics of eukaryotes. Biological and molecular evolution / Humans / Hypoxia / Kidney cancer / kidney cysts / Kidney Diseases, Cystic - genetics / Kidney Diseases, Cystic - pathology / Kidney Neoplasms - genetics / Kidney Neoplasms - pathology / Kidneys / Kinases / LOH / loss of heterozygosity / mammalian target of rapamycin / Mechanistic Target of Rapamycin Complex 1 / Medical genetics / Medical sciences / Mice / Mice, Transgenic / Mitogen-Activated Protein Kinase 3 - metabolism / Molecular and cellular biology / molecular genetics / mTOR / mTORC1 / Multiprotein Complexes / Mutation / Nephrology. Urinary tract diseases / oncology / Precancerous Conditions - genetics / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - physiology / RCC / RCND / renal adenocarcinoma / renal cell carcinoma / renal cysadenocarcinoma and nodular dermatofibrosis / renal medicine / Ribosomal Protein S6 Kinases - metabolism / SEM / standard error of the mean / Syndrome / TOR Serine-Threonine Kinases / Transcription Factors - metabolism / TSC / tuberous sclerosis complex / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - physiology / Tumors / Tumors of the urinary system / VHL / von Hippel Lindau / β-galactosidase-neomycin-phosphotransferase II / β-geo