201163

FLCN

BHD|FLCL;folliculin;FLCN;folliculin

BHD skin lesion fibrofolliculoma protein|birt-Hogg-Dube syndrome protein

17p11.2

protein-coding

Count: 3; Pubmed_search,Generif,UniProt

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. 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 BHD tumor suppressor activity, we generated mutant Bhd mice and embryonic stem cell lines. BHD-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 deficiency in Bhd(-/-) cells is not a consequence of elevated mTOR or ERK activity, but results instead from reduced Bim transcription associated with a general loss of TGFbeta-mediated transcription and chromatin modifications. In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFbeta-dependent transcription and apoptosis, which has implications for the development of targeted therapies.

BACKGROUND: Germline mutations in a tumor suppressor gene FLCN lead to development of fibrofolliculomas, lung cysts and renal cell carcinoma (RCC) in Birt-Hogg-Dube syndrome. TFE3 is a member of the MiTF/TFE transcription factor family and Xp11.2 translocations found in sporadic RCC involving TFE3 result in gene fusions and overexpression of chimeric fusion proteins that retain the C-terminal DNA binding domain of TFE3. We found that GPNMB expression, which is regulated by MiTF, was greatly elevated in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Since TFE3 is implicated in RCC, we hypothesized that elevated GPNMB expression was due to increased TFE3 activity resulting from the inactivation of FLCN. METHODOLOGY/PRINCIPAL FINDINGS: TFE3 knockdown reduced GPNMB expression in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Moreover, FLCN knockdown induced GPNMB expression in FLCN-restored renal cancer cells. Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization as revealed by elevated GPNMB mRNA and protein expression, and predominantly nuclear immunostaining of TFE3 in renal cancer cells, mouse embryo fibroblast cells, mouse kidneys and mouse and human renal tumors. Nuclear localization of TFE3 was associated with TFE3 post-translational modifications including decreased phosphorylation. CONCLUSIONS/SIGNIFICANCE: Increased TFE3 activity is a downstream event induced by FLCN inactivation and is likely to be important for renal tumor development. This study provides an important novel mechanism for induction of TFE3 activity in addition to TFE3 overexpression resulting from Xp11.2 translocations, suggesting that TFE3 may be more broadly involved in tumorigenesis.

The Birt-Hogg-Dube (BHD) syndrome is an inherited genodermatosis characterized by a predisposition to hamartomatous skin lesions, pulmonary cysts, and renal carcinoma. Seventy-seven renal tumors from 12 patients with germline BHD mutations were examined by DNA sequencing to identify somatic mutations in the second copy of BHD. Sequence alterations were detected in the majority of renal tumors (41 of 77, 53%), with loss of heterozygosity at the BHD locus in a minority of additional tumors (14 of 77, 17%). The somatic mutations were distributed across the entire gene, and the majority resulted in frameshifts that are predicted to truncate the BHD protein. These results support a role for BHD as a tumor suppressor gene that predisposes to the development of renal tumors when both copies are inactivated.

Over the past decade cancer-causing genes have been identified for the most common histologic types of renal cancer, specifically clear cell, papillary type 1 and papillary type 2. Genes predisposing to the more rare chromophobe renal carcinoma and renal oncocytoma were unknown until the recent discovery of a novel gene, BHD, on chromosome 17p that was found to be mutated in the germline of affected family members with the Birt-Hogg-Dube (BHD) syndrome. These patients develop the hallmark BHD skin lesions (fibrofolliculomas), lung cysts and spontaneous pneumothorax. Importantly, BHD patients have an increased risk for developing a variety of renal neoplasia, most commonly chromophobe and oncocytic hybrid tumors. This review will describe the phenotypic manifestations of BHD including the histologic features of BHD-associated renal tumors, the identification of this novel renal cancer-predisposing gene, the BHD mutation spectrum found in BHD patients, and will discuss the potential role of BHD as a tumor suppressor gene.