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Birt–Hogg–Dubé Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Marianne Geilswijk, Mette Sommerlund, Mia Gebauer Madsen, Anne-Bine Skytte, Elisabeth Bendstrup
The functions of the folliculin protein (FLCN) are not fully understood. In silico, in vitro, and in vivo studies of both human and animal materials have shown that FLCN is involved in several fundamental cellular mechanisms. In fact, FLCN acts not only as a tumor suppressor but also a protein required for ciliogenesis, cell adhesion, and autophagy, through its interaction with folliculin-interaction-protein-1 and -2 (FNIP1 and FNIP2) separately or in conjunction [12,13].
Role of metabolomics-derived biomarkers to identify renal cell carcinoma: a comprehensive perspective of the past ten years and advancements
Published in Expert Review of Molecular Diagnostics, 2020
Ashish Gupta, Kavindra Nath, Navneeta Bansal, Manoj Kumar
Another cause of RCC is the cell surface receptor MET for ligand hepatocyte growth factor (HGF) induction. HGF targets MET to induce the signal for phosphorylation of LKB1 through a Raf cascade. AMPK, the primary energy sensor, binds a complex FLCN-FNIP1-FNIP2. FLCN is phosphorylated by a rapamycin-sensitive kinase such as the mTOR. The TSC1-TSC2 complex interacts with the modulation of mTOR. While the cell feels energy deficiency, AMPK activates TSC2 and impedes the activity of mTOR. With this cascade, uncoupling AMPK energy-sensing regulates the mTOR expression. The LKB1-AMPK cascade is phosphorylated to TSC1-TSC2. Using this cascade, the cell’s response to energy and nutrient sensing [1,3]. On the other side, the fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes encode mitochondrial tricarboxylic acid (TCA) cycle enzymes. FH and SDH have an essential role in cellular energy production. Dormancy of FH or SDH weakens the PHD activity and epitomizes a VHL-free cascade for the deregulation of HIF degeneration [1,3].
HSP90 and Co-chaperones: Impact on Tumor Progression and Prospects for Molecular-Targeted Cancer Therapy
Published in Cancer Investigation, 2020
Ameneh Jafari, Mostafa Rezaei-Tavirani, Behrouz Farhadihosseinabadi, Shahrouz Taranejoo, Hakimeh Zali
Several other tumor suppressors have also been reported to depend on Hsp90 including SDH, FLCN, TSC1/2, large tumor suppressor kinase 1 (LATS1), and LATS2. In this context, Succinate dehydrogenase (SDH) is a component of the respiratory chain complexes and responsible for energy metabolism. The mitochondrial paralogue of HSP90, TRAP1, promotes neoplastic growth by binding and inhibiting SDH, consequently led to respiratory down-regulation and succinate accumulation. Then succinate stabilizes HIF1α and promotes neoplastic development (62). Folliculin (FLCN) tumor suppressor has been introduced as an HSP90 client protein (63). This protein interacts with folliculin-interacting proteins 1 and 2 (FNIP1/FNIP2), which act as co-chaperones and are essential for FLCN tumor suppressive function (63,64). It displayed FNIPs decelerate chaperone cycle, facilitating FLCN-HSP90 interaction, subsequently ensuring FLCN stability (63). The TSC1 and TSC2 tumor suppressors cause tuberous sclerosis complex (TSC), a genetic syndrome that result in the appearance of benign tumors in the brain and other organs (65). Woodford et al. have recently shown that TSC2 is a client of HSP90, since treatment of cells with HSP90 inhibitors results in ubiquitination and proteasomal degradation of TSC2 (66). The authors have also suggested TSC1 as a new HSP90 co-chaperone that inhibits its ATPase activity. This study shown Tsc1 facilitates HSP90-mediated folding of both kinase clients, such as c‐Src, ErbB2, Raf‐1, and Cdk4 and nonkinase clients such as TSC2 and FLCN (66). Tumor suppressors LATS1 and LATS2 are HSP90 clients that relay antiproliferative signals in the Hippo tumor suppressor pathway. HSP90 inhibitors can disrupt the LATS tumor suppressor pathway in human cancer cells (67).