RT Journal Article
SR Electronic
T1 Renal tumour suppressor function of the Birt–Hogg–Dubé syndrome gene product folliculin
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 182
OP 189
DO 10.1136/jmg.2009.072009
VO 47
IS 3
A1 V Hudon
A1 S Sabourin
A1 A B Dydensborg
A1 V Kottis
A1 A Ghazi
A1 M Paquet
A1 K Crosby
A1 V Pomerleau
A1 N Uetani
A1 A Pause
YR 2010
UL http://jmg.bmj.com/content/47/3/182.abstract
AB Background Renal 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 Methods Here, 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.Conclusion In 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.