Abstract
The Birt–Hogg–Dubé (BHD) disease is a genetic cancer syndrome. The responsible gene, BHD, has been identified by positional cloning and thought to be a novel tumor suppressor gene. BHD mutations cause many types of diseases including renal cell carcinomas, fibrofolliculomas, spontaneous pneumothorax, lung cysts, and colonic polyps/cancers. By combining Gateway Technology with the Ksp-Cre gene knockout system, we have developed a kidney-specific BHD knockout mouse model. BHDflox/flox/Ksp-Cre mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. The affected BHDflox/flox/Ksp-Cre mice died of renal failure at approximate three weeks of age, having blood urea nitrogen levels over tenfold higher than those of BHD flox/+/Ksp-Cre and wild-type littermate controls. We further demonstrated that these phenotypes were caused by inactivation of BHD and subsequent activation of the mTOR pathway. Application of rapamycin, which inhibits mTOR activity, to the affected mice led to extended survival and inhibited further progression of cystogenesis. These results provide a correlation of kidney-targeted gene inactivation with renal carcinoma, and they suggest that the BHD product FLCN, functioning as a cyst and tumor suppressor, like other hamartoma syndrome–related proteins such as PTEN, LKB1, and TSC1/2, is a component of the mTOR pathway, constituting a novel FLCN-mTOR signaling branch that regulates cell growth/proliferation.
Highlights
Birt–Hogg–Dube (BHD) syndrome is an autosomal dominant genetic disease characterized by fibrofolliculomas, renal cell carcinomas, spontaneous pneumothorax, and lung cysts[1]
To elucidate the biochemical mechanisms of the cystogenesis and carcinogenesis related to inactivation of the BHD gene, we investigated the possible relevance of BHD to the mTOR signaling pathway for the following reasons: 1) our microarray analysis revealed that ectopic expression of the BHD gene product, FLCN, led to down-regulation of the AKT- related mTOR pathway signature (Figure S2); 2) BHD, PTEN, LKB1, and TSC1/2 are all hamartoma syndrome–related genes, and the roles of PTEN, LKB1, and TSC1/ 2 in the mTOR pathway have been well-established; and 3) in vitro experiments indicated that FLCN interacted with AMPK, a member of the mTOR pathway [18]
We provide the first evidence that the BHD protein FLCN predominantly expresses in the proximal tubules and collecting ducts of the renal cortex (Figure 3K–N)
Summary
Birt–Hogg–Dube (BHD) syndrome is an autosomal dominant genetic disease characterized by fibrofolliculomas (follicular hamartomas), renal cell carcinomas, spontaneous pneumothorax, and lung cysts[1]. While PTEN, LKB1, and TSC1/2 are critical members of the mTOR pathway [17], the BHD protein FLCN has been suggested to be involved [18,19]. These findings imply that FLCN, like PTEN, may be a pivotal tumor suppressor gene and a potential player in mTOR pathway. An in vitro experiment revealed that FLCN interacts with AMPK in mammalian cell lines, associating FLCN with the mTOR pathway[18], whereas in fission yeast, Bhd was reported to activate the mTOR counterpart Tor, presenting an opposite role to Tsc1/2[19]
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