This week we highlight the work of Dr Tim Cash, who worked on BHD syndrome as part of his PhD studies in the lab of Professor Celeste Simon at the Abramson Family Cancer Research Institute, University of Pennsylvania. Dr Cash became interested in BHD syndrome after working on the related syndrome Tuberous Sclerosis complex (TSC) in the lab of Professor Elizabeth Henske at the Fox Chase Cancer Center in Philadelphia.
Dr Cash’s work focused on identifying the biological role of FLCN. In 2011, Cash et al. showed that FLCN was involved in the regulation of apoptosis through the TGF-β signalling pathway. Cells that lacked FLCN were resistant to cell death and this was thought to be due to the dysregulation of pro-apoptotic proteins. This paper has been reviewed in a previous blog post. Lim et al. (2012) have recently found FLCN, FNIP2 and AMPK to be involved in MNU-induced apoptosis, further highlighting the link between FLCN and cell death. Read more about this paper and how apoptosis could be implicated in the pathogenesis of BHD syndrome in last week’s blog post.
In addition to TGF-β signalling, Dr Cash worked on the link between FLCN and mTORC1 activity, demonstrating that downregulation of FLCN leads to mTOR inhibition (Hartman et al., 2009). Furthermore, renal tumours in mice carrying a FLCN mutation had low levels of phosphorylated S6, suggesting low levels of mTOR activity and adding to the debate on how FLCN affects mTOR signalling, which is described in more detail here.
Dr Cash submitted his PhD thesis, entitled ‘Molecular mechanisms of the Birt-Hogg-Dubé tumor suppressor’, in 2010 and has now moved to a postdoctoral position at the CNIO in Madrid where he is focusing on cellular aging and metabolism. Watch our video interview, filmed at the Third BHD Symposium, to learn more about Dr Cash and his BHD work. A transcript and audio-only file are also available for this interview.
To learn more about current BHD research and to meet researchers working on BHD syndrome, attend the Fourth BHD Symposium, to be held in Cincinnati on 28th-30th March 2012. The meeting will include sessions for patients and researchers. Registration and abstract submission are now open and more information can be found here. We hope to see you in Cincinnati!
- 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, 30 (22), 2534-46 PMID: 21258407
- Hartman TR, Nicolas E, Klein-Szanto A, Al-Saleem T, Cash TP, Simon MC, & Henske EP (2009). The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis. Oncogene, 28 (13), 1594-604 PMID: 19234517
- Lim TH, Fujikane R, Sano S, Sakagami R, Nakatsu Y, Tsuzuki T, Sekiguchi M, & Hidaka M (2011). Activation of AMP-activated protein kinase by MAPO1 and FLCN induces apoptosis triggered by alkylated base mismatch in DNA. DNA repair PMID: 22209521