Introducing TFE3 to the FLCN pathway

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.


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  • 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
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