The cell cycle is a tightly controlled process, requiring both oncogenes, which drive cell division and growth, and tumour suppressor genes, which prevent cells from growing and dividing too quickly. BHD Syndrome is caused by autosomal dominant mutations in the FLCN gene; given that a common characteristic of all three symptoms of BHD – fibrofolliculoma, lung cysts and kidney cancer – is hyperplasia, it is thought that FLCN is a tumour suppressor. Further evidence supporting this assertion is that somatic loss of the remaining wild type FLCN allele seems to be required for kidney cancer progression in BHD (Vocke et al., 2005).
A recent study by Kawai et al. found that FLCN regulates cyclin D1 expression. Cyclin D1 promotes G1 to S phase progression in the cell cycle, and its overexpression has been found in a number of cancers (Fu et al., 2004). Kawai et al. found that RNAi knock-down of FLCN in HeLa cells led to increased cyclin D1 expression and, conversely, that reintroduction of the FLCN gene into FLCN-null Nihon rat kidney tumour cells reduced cyclin D1 expression. Taken together, these results suggest that FLCN inhibits cyclin D1 expression and, by extension, may also regulate G1 to S phase transition of the cell cycle.
The authors subsequently found that FLCN exerts its control on cyclin D1 expression post-transcriptionally and that the central portion of cyclin D1’s 3’ untranslated region (3’UTR) is necessary for this regulation. A number of micro RNAs and three RNA binding proteins (RBPs) – HuR, AUF1 and hnRNP l – are known, or predicted, to target this portion of cyclin D1’s 3’UTR and modify its expression. However, none of these candidates appeared to be required for FLCN-dependent cyclin D1 inhibition, although these experiments cannot rule out a role for unknown miRNAs and RBPs. Interestingly the authors found that treatment of cells with wortmannin and rapamycin (also known as Sirolimus) abrogated the effects of FLCN knock-down on cyclin D1 expression, suggesting that FLCN’s regulation of cyclin D1 expression may be exerted via the PI3K and mTOR signalling pathways. Indeed, combined therapy for mantle cell lymphoma (MCL), which is caused by a chromosomal translocation resulting in overexpression of cyclin D1, with a dual inhibitor of the PI3K and mTOR pathways is showing promising results in vitro, suggesting that this may also prove a viable therapy for BHD patients in the future (Kim et al., 2012).
FLCN has been previously been linked to cell cycle control. Firstly, FLCN is found to be differentially phosphorylated throughout the cell cycle, suggesting that its role may change during the cell cycle, as described here. Furthermore, as discussed in this blog post, FLCN has been found to regulate RhoA signalling, which is also involved in the G1 to S phase transition of the cell cycle and regulates cyclin D1 activity (Mammoto et al., 2004; Watts et al., 2006). Additionally, FLCN is known to be an important regulator of apoptosis (as reviewed here) – a common outcome of tumour suppressor action when cell cycle regulation breaks down. It will be interesting to find out how FLCN’s role in cyclin D1 inhibition relates to its known roles in RhoA regulation and apoptosis, and whether these studies show snapshots of different portions of a single, large, cell cycle regulation pathway, or whether FLCN functions independently in multiple pathways in order to fine tune cell cycle regulation.
- Fu M, Wang C, Li Z, Sakamaki T, Pestell RG (2004). Minireview: Cyclin D1: normal and abnormal functions. Endocrinology, 145 (12), 5439-47 PMID: 15331580
- Kawai A, Kobayashi T, & Hino O (2013). Folliculin regulates cyclin D1 expression through cis-acting elements in the 3′ untranslated region of cyclin D1 mRNA. International journal of oncology PMID: 23525507
- Kim A, Park S, Lee JE, Jang WS, Lee SJ, Kang HJ, Lee SS (2012). The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells. Leukemia Research, 36 (7), 912-20 PMID: 22560334
- Mammoto A, Huang S, Moore K, Oh P, Ingber DE (2004). Role of RhoA, mDia, and ROCK in cell shape-dependent control of the Skp2-p27kip1 pathway and the G1/S transition. Journal of Biological Chemistry, 279 (25), 6323-30 PMID: 15096506
- Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, Linehan WM (2005). High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. Journal of the National Cancer Institute, 97 (12), 931-5 PMID: 15956655
- Watts KL, Cottrell E, Hoban PR, Spiteri MA (2006). RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis. Respiratory Research, 7 (88), PMID: 16776827
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.