Recent research into the function of Folliculin has been carried out in the context of renal tumourigenesis using BHD animal models. Research has implicated Folliculin in the PI3K-AKT and mTOR signalling pathways and specifically interacting with AMPK, FNIP1 and FNIP2 (Baba et al, 2006; Hasumi et al 2008; Takagi et al, 2008). Is dysfunction of this role specific to renal tumourigenesis, or can it be applied to pulmonary cyst formation too?
We could speculate that the mechanism underlying renal tumourigenesis is a multi-step process where renal cysts develop initially and the accumulation of genetic instability results in tumourigenesis and the development of malignant renal tumours. However if this process is ‘universal’ how do we explain the absence of pulmonary tumours in BHD syndrome? So, the question of why pulmonary cysts do not develop into pulmonary tumours remains unanswered.
One suggestion would be that the lung cysts rupture once they are a certain size, preventing the transition to tumourigenic growth. Why cyst development is specific to the outer surface of the lungs is also an outstanding issue, since renal tumours are multifocal. One idea is that the mechanism instigating cystic growth through to tumourigenic development is the same in the lung and the kidney, but that pulmonary tumours never develop due to cyst rupture. Alternatively, could each organ have a specific mechanism which would result in the different phenotypes?
How do we shed light on what is happening in the BHD lung? One method could be to examine the underlying mechanism of pulmonary tumourigenesis in incidences known to have a genetic component in order to uncover dysfunctions in non-BHD related cell signalling pathways, or lung specific tumour suppressors or oncogenes, that might be potentially implicated in BHD syndrome.
Tobacco use accounts for up to 90% of lung cancer incidence, however the remaining 10% of cases are thought to have a genetic or familial component (Peto et al, 2006). A major familial lung cancer susceptibility locus was first identified in 2004 (Bailey-Wilson et al,) using genome wide linkage analysis to identify the major susceptibility locus. Fine-mapping of the region, subsequently, by You et al, (2009) determined that the RGS17 gene was over-expressed in familial lung cancer.
RGS17 encodes a member of the regulator of G-protein signalling family. This protein contains a conserved, 120 amino acid motif called the RGS domain and a cysteine-rich region. The protein attenuates the signalling activity of G-proteins by binding to activated, GTP-bound G alpha subunits and acting as a GTPase activating protein, increasing the rate of conversion of the GTP to GDP. As well as being associated with lung cancer, RGS17 has been shown to be over expressed in prostate cancer, associated with its ability to promote cyclic AMP (cAMP)-responsive element binding protein (CREB)-responsive gene expression, increase cAMP levels, and enhance forskolin-mediated cAMP production (James et al, 2009).
Ultimately, studies such as those by You et al, (2009) contribute further to our understanding of lung cancer susceptibility but since research into the pathogenic mechanism of RGS17 is fairly recent, how it contributes to pulmonary tumourigenesis is still unknown. However, by maintaining an awareness of RGS17 research, we might gain insights into potentially insightful elements of pulmonary tumourigenesis which may shed light on the mechanisms underlying the pulmonary phenotype of BHD Syndrome.
www.bhdsyndrome.org – the online reference site for anyone interested in BHD Syndrome
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Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, Zhang D, Abe M, Hagiwara Y, Takahashi K. and Hino O, Interaction of folliculin (Birt–Hogg–Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein, Oncogene 27 (2008), pp. 5339–5347.
You et al, 2009; Fine Mapping of Chromosome 6q23-25 Region in Familial Lung Cancer Families Reveals RGS17 as a Likely Candidate Gene. Clinical Cancer Research April 2009 15; 2666.