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Background  Germline mutations in the  FLCN  gene are responsible for the development of fibrofolliculomas, lung cysts and renal neoplasia in Birt-Hogg-Dube' (BHD) syndrome. The encoded protein folliculin (FLCN) is conserved across species but contains no classic motifs or domains and its function remains unknown. Somatic mutations or loss of heterozygosity in the remaining wild type copy of the  FLCN  gene have been found in renal tumors from BHD patients suggesting that  FLCN  is a classic tumor suppressor gene.    Results  To examine the tumor suppressor function of  FLCN , wild-type or mutant  FLCN  (H255R) was stably expressed in a  FLCN-null  renal tumor cell line, UOK257, derived from a BHD patient. When these cells were injected into nude mice, tumor development was inversely dependent upon the level of wild-type  FLCN  expression. We identified genes that were differentially expressed in the cell lines with or without wild-type  FLCN , many of which are involved in TGF-β signaling, including  TGF-β2  ( TGFB2 ) , inhibin β A chain  ( INHBA ) , thrombospondin 1  ( THBS1 ),  gremlin  ( GREM1 ), and  SMAD3 . In support of the  in vitro  data,  TGFB2 ,  INHBA ,  THBS1  and  SMAD3  expression levels were significantly lower in BHD-associated renal tumors compared with normal kidney tissue. Although receptor mediated SMAD phosphorylation was not affected, basal and maximal TGF-β-induced levels of  TGFB2 ,  INHBA  and  SMAD7  were dramatically reduced in  FLCN-null  cells compared with  FLCN -restored cells. Secreted TGF-β2 and activin A (homo-dimer of INHBA) protein levels were also lower in  FLCN-null  cells compared with  FLCN -restored cells. Consistent with a growth suppressive function, activin A (but not TGF-β2) completely suppressed anchorage-independent growth of  FLCN-null  UOK257 cells.    Conclusions  Our data demonstrate a role for  FLCN  in the regulation of key molecules in TGF-β signaling and confirm deregulation of their expression in BHD-associated renal tumors. Thus, deregulation of genes involved in TGF-β signaling by  FLCN  inactivation is likely to be an important step for tumorigenesis in BHD syndrome.

Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-β signaling