TGF-β signalling and apoptotic resistance

In two separate posts in June and July last year, Duncan discussed a paper by Hong et al. (2010), which demonstrated that a loss of FLCN affected TGF-β signalling. This particular finding has now been expanded upon by experiments which show that FLCN also regulates apoptosis through TGF-β-mediated transcription in mouse embryonic stem (ES) cells (Cash et al., 2011).

In this study, Cash et al. established a FLCN-null ES cell line, and saw that not only were these cells smaller than their wild-type and heterozygous counterparts, but they also appeared to be resistant to cell-intrinsic apoptotic cues.

This led the authors to investigate various cell-intrinsic mediators of apoptosis, such as the Bcl2 family, and they discovered that a variety of pro-apoptotic proteins were misregulated in the FLCN-null ES cells. In particular, a protein called Bim was significantly down-regulated, and treatment with a chemical mimetic, or restoration of Bim/FLCN expression, rescued the anti-apoptotic phenotype of these ES cells. Interestingly, some autophagy inhibitors also rescued the apoptotic response in these cells. Additionally, less Bim protein was also detected in BHD tumours from both mice and humans, indicating that this phenomenon may be a common event in BHD-related tumourigenesis.

Bim is regulated by numerous processes, but it is unclear which signalling mechanisms are specifically involved in the dysregulation of Bim expression in the FLCN-null ES cells. Experiments using inhibitors of mTOR and MEK-ERK signalling demonstrated that these pathways were not involved in the regulation of Bim expression and apoptosis in these cells. Further experiments by Cash et al. also showed that the eIF2α signalling pathway was not involved.

The authors then analysed TGF-β signalling, and saw that a particular TGF-β ligand specifically upregulated Bim expression only when FLCN was expressed. Additionally, TGF-β signalling appeared to regulate numerous other genes involved in apoptosis, the cell cycle and differentiation. Furthermore, within the FLCN-null ES cells, they saw hypo-acetylation of specific TGF-β target gene promoters, and that treatment with a histone deacetylase (HDAC) inhibitor restored the mRNA levels of multiple TGF-β target genes, as well as Bim protein levels and the cell death response.

Together, these results could help further explain the multiple phenotypes observed in BHD syndrome, as well as suggesting novel therapies, such as chemical mimetics, autophagy inhibitors and HDAC inhibitors, some of which are already in clinical use for other types of cancers.

  • Cash TP, Gruber JJ, Hartman TR, Henske EP, Simon MC (2011). Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFβ-mediated transcription. Oncogene. 2011 Jan 24. [Epub ahead of print]
  • Hong SB, Oh H, Valera VA, Stull J, Ngo DT, Baba M, Merino MJ, Linehan WM, Schmidt LS (2010). Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Mol Cancer. Jun 23;9(1):160.

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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