It is an exciting time for the BHD community, as the pace of BHD research increases ever more. In view of this, it would be of note to discuss another study by Hong et al. (2010), which sheds yet more light on FLCN and its interactions in the context of BHD syndrome.

In this paper, the authors used cultured UOK257 cells, FLCN knock-out mice and BHD patient tumours to show that FLCN inactivation increases TFE3 activity. TFE3 is a part of the MiTF/TFE transcription factor family, and chromosomal translocations involving this gene are seen to be involved in juvenile renal cell carcinoma (Armah & Parwani, 2010).

What is particularly interesting is that a loss of FLCN appears to modify the localisation of TFE3, making it largely nuclear. Furthermore, this nuclear localisation is correlated with post-translational modifications of TFE3, such as decreased phosphorylation and an increased level of a larger TFE3 isoform (which is potentially a product of a post translational modification). This is the first time that the specific regulation of TFE3 nucleocytoplasmic shuttling has been documented, and it is thought that this modulation of TFE3 activity could help contribute to the development of the kidney cancers seen in BHD syndrome.

Their work also demonstrated that GPNMB, a glycosylated transmembrane protein and TFE3 target gene, was upregulated by FLCN inactivation. This protein is involved in cancer cell progression in a number of different organ systems (Kuan et al., 2006; Tse et al., 2006; Rose et al., 2010), and the authors suggest that it could be used as an effective tumour biomarker or drug target in BHD syndrome. Several lysosomal genes were also observed to be regulated by TFE3 and FLCN, and it would be interesting to see if lysosomal biogenesis and function are also impaired in BHD syndrome.

• Armah HB, & Parwani AV (2010). Xp11.2 translocation renal cell carcinoma. Archives of pathology & laboratory medicine, 134 (1), 124-9 PMID: 20073616
• Hong SB, Oh H, Valera VA, Baba M, Schmidt LS, & Linehan WM (2010). Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PloS one, 5 (12) PMID: 21209915
• Kuan CT, Wakiya K, Dowell JM, Herndon JE 2nd, Reardon DA, Graner MW, Riggins GJ, Wikstrand CJ, & Bigner DD (2006). Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clinical cancer research : an official journal of the American Association for Cancer Research, 12 (7 Pt 1), 1970-82 PMID: 16609006
• Rose AA, Grosset AA, Dong Z, Russo C, Macdonald PA, Bertos NR, St-Pierre Y, Simantov R, Hallett M, Park M, Gaboury L, & Siegel PM (2010). Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 16 (7), 2147-56 PMID: 20215530
• Tse KF, Jeffers M, Pollack VA, McCabe DA, Shadish ML, Khramtsov NV, Hackett CS, Shenoy SG, Kuang B, Boldog FL, MacDougall JR, Rastelli L, Herrmann J, Gallo M, Gazit-Bornstein G, Senter PD, Meyer DL, Lichenstein HS, & LaRochelle WJ (2006). CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 12 (4), 1373-82 PMID: 16489096