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Characterising the Tumour Suppression Function of Folliculin

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Characterising the Tumour Suppression Function of Folliculin Characterising the Tumour Suppression Function of Folliculin Rachael Preston 0740708 Thesis submitted for the degree of Doctor of Philosophy 1 Abstract Birt–Hogg–Dubé (BHD) syndrome is a rare inherited autosomal dominant disorder first described by Birt, Hogg and Dube in 1977 (Birt et al,. 1977). BHD affects approximately 100 families worldwide. Approximately one third of diagnosed BHD patients also develop renal cell carcinoma (RCC) (Schmidt et al., 2005). BHD arises as a result of loss of function of the Folliculin protein expressed from the BHD gene, suggesting than Folliculin serves as a tumour suppressor (Vocke et al., 2005). Although it is considered that FLCN represses cell growth, the role that FLCN plays in cancer progression and/or initiation is currently unresolved. It has been observed that tumours taken from BHD patients have reduced levels of mitochondria (Yang et al., 2008). Previous studies have also suggested that aberrant levels of mTOR activity are observed in Folliculin-deficient cell lines (Baba et al., 2006; Baba et al., 2008). Aberrant levels of mTORC1 activity have been associated with increased levels of Hypoxia inducible factor transcriptional activity, decreased autophagic activity (Land and Tee, 2007; Hands et al., 2009). There are several genes within the mTOR pathways which act as Tumour Suppressors. Mutations within these genes result in inherited genetic disorders, including Tuberous, Sclerosis complex (TSC). Loss of function of TSC1/TSC2 results in TSC which is clinically similar to BHD (Gomez et al., 1999). Arbarrant levels of mitochondrial biogeneisis and HIF activity have been observed in cells deficient in TSC1 ad TSC2 (Land and Tee, 2007; Chen et al., 2008). Increased levels of mTORC1 activity have also been shown to result in decreased levels of autophagic activity in TSC2 deficient cells (Parkhitko et al., 2011). In order to characterise the tumour suppression function of Folliculin, the effects of loss of function of Folliculin on mitochondrial biogenesis and mitochondrial function, hypoxia inducible factor (HIF) transcriptional activity, and autophagic activity were investigated using multiple cell lines. The results from this study suggest that loss of function of FLCN results in increased production of ROS species. This leads to compromised mitochondrial membrane potential and decreased ATP production as a result of increased expression of uncoupling proteins in order to try and reduce the increased levels of ROS. FLCN is also phosphorylated at multiple residues by both mTORC1 and AMPK and activity of both mTORC1 and AMPK is increased in response to the depleted ATP levels as a result of increased UCP production in response to the increased ROS production observed upon loss of functional FLCN. This results in increased levels of mitochondrial biogenesis and increased levels of glycolytic activity via increased activation of HIFα proteins in order to compensate for this energy deficit. Furthermore, it appears that both mTORC1 and AMPK could drive HIF transcription and mitochondrial biogenesis through modulation of FLCN phosphorylation. ULK-mediated autophagy also appears to be upregulated upon loss of functional FLCN, possibly as a result of the increased levels of AMPK activation in order to provide a protection for these cells. This may be via the catabolising the dysfunctional mitochondria observed in cells upon loss of BHD, a process which may be exploited as a potential therapeutic target for BHD patients. Further investigations into these cellular processes may also provide clues to potential therapeutic targets for treatment of BHD patients. 2 Contents 1 Introduction ....................................................................................................................................... 11 1.1 Birt-Hogg-Dube Syndrome. ......................................................................................................... 11 1.2 Folliculin ...................................................................................................................................... 11 1.3 Animal models of BHD ................................................................................................................ 12 1.3.1 The Rat model of BHD .......................................................................................................... 12 1.3.2 The Dog model of BHD ......................................................................................................... 12 1.3.3 The Drosophila melanogaster model of BHD....................................................................... 13 1.3.4 The S. pombe model of BHD ................................................................................................ 13 1.3.5 Mouse models of BHD ......................................................................................................... 13 1.4 The UOK257 cell line ................................................................................................................... 14 1.5 Genetic studies of BHD ............................................................................................................... 15 1.5.1 Mutations of the BHD gene in BHD patients ....................................................................... 15 1.5.2 Geneotype – phenotype correlation studies in BHD patients ............................................ 16 1.6 Signalling pathways which are regulated by FLCN ...................................................................... 20 1.6.1 The Raf-MEK-Erk pathway ................................................................................................... 20 1.6.2 JAK/STAT signalling .............................................................................................................. 20 1.6.3 TGF-β signalling and transcriptional control ........................................................................ 21 1.7 FLCN-binding proteins ................................................................................................................. 21 1.8 Tumour suppressors ................................................................................................................... 22 1.8.1 Tumour suppressors and apoptosis ..................................................................................... 22 1.8.2 Tumour suppressors and cellular senescence ..................................................................... 23 1.9 The mTOR signalling pathway. .................................................................................................... 24 1.10 mTOR signalling and cancer. ..................................................................................................... 28 1.11 Tumour suppressor genes within the mTOR pathway ............................................................. 29 1.11.1 Tuberous Sclerosis Complex. ............................................................................................. 30 1.11.5 Von-Hippel-Lindau disease ................................................................................................ 31 1.12 Constitutive activation of mTORC1 may also contribute to the development of tumours in BHD patients. .................................................................................................................................... 32 1.13 FLCN is differentially phosphorylated by AMPK and mTOR. .................................................... 33 1.14 AMPK and cancer ...................................................................................................................... 35 1.15 Both AMPK and mTOR positively regulate mitochondrial biogenesis ...................................... 35 1.16 Both AMPK and mTOR positively regulate Hypoxia Inducible Factor transcriptional activity . 36 3 1.17 AMPK activation results in increased autophagic activity. ....................................................... 37 1.18 Renal cell carcinomas. ............................................................................................................... 40 1.18.1 Clear cell renal cell carcinomas .......................................................................................... 40 1.18.2 Chromophobe renal cell carcinomas. .............................................................................. 40 1.18.3 Papillary renal cell carcinomas ........................................................................................... 40 1.18.4 Oncocytomas ..................................................................................................................... 41 1.18.5 Renal cell carcinoma syndromes, mitochondrial dysfunction and aberrant HIF signalling. ...................................................................................................................................................... 41 1.19 Cyst formation .......................................................................................................................... 42 1.19.1 Polycystic kidney disease ................................................................................................... 42 1.19.1 Ciliopathy and renal cyst formation ................................................................................... 43 1.19.2 mTOR signalling and cystogenesis. .................................................................................... 43 1.20 Aims and Objectives of this Project .......................................................................................... 44 2 The effect
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