Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia

Jindong Chen*, Kunihiko Futami, David Petillo, Jun Peng, Pengfei Wang, Jared Knol, Yan Li, Sok Kean Khoo, Dan Huang, Chao Nan Qian, Ping Zhao, Karl Dykyma, Racheal Zhang, Brian Cao, Ximing J. Yang, Kyle Furge, Bart O. Williams, Bin Tean Teh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

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.

Original languageEnglish (US)
Article numbere3581
JournalPloS one
Volume3
Issue number10
DOIs
StatePublished - Oct 30 2008

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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