| Birt-Hogg-Dube (BHD) syndrome is an inherited cancer susceptibility disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from loss-of-function mutations in the BHD gene which encodes the protein product Folliculin. BHD is also inactivated in a significant fraction of patients with sporadic renal cancers and idiopathic cystic lung disease, and little is known about its mode of action. To investigate the molecular and cellular basis of Folliculin's tumor suppressor activity, we generated mutant Bhd mice and embryonic stem cell lines. Folliculin-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim, which was similarly observed in all human and murine BHD-related tumors examined. We further demonstrate that Bim protein deficiency in Bhd-/- cells is not a consequence of elevated mTOR or ERK activity, but results instead from reduced Bim transcription associated with altered TGFbeta-mediated chromatin modifications. In aggregate, this work identifies a specific tumor suppressive mechanism for Folliculin in regulating TGFbeta dependent apoptosis, which has implications for the development of targeted therapies. Future efforts aim to define how Folliculin regulates TGFbeta-mediated chromatin modifications and transcriptional output. |
