Phosphorylation of FLCN and FNIP1 was regulated by AMPK and mTOR routines suggesting a functional rela tionship using the AMPK mTOR pathway. Interestingly, activation of mTOR downstream signaling molecules was witnessed in kidney targeted BHD conditional knockout mouse kidneys. Also, the renal tumors from BHD individuals showed elevated phosphorylation of mTOR. In contrast to these results, it was suggested that yeast homologs of FLCN and TSC1/2 might have opposing roles in amino acid homeostasis. The cysts and renal tumors derived through the Flcn heterozygous mice described by Hartman et al. showed diminished phos pho S6R suggesting diminished mTOR activation. On the flip side Hasumi and coworkers located upregu lation of both mTORC1 and mTORC2 pathways in child ney tumors from Flcnd/ mice. Hudon et al. suggest that up or down regulation of mTOR by inactivation of Flcn in a mouse model might be context dependent.
Thus it truly is possible that mTOR signaling is regulated dif ferently full report by FLCN based on cell kinds or experimen tal circumstances. A renal cancer cell line established from a BHD patient was recently produced and characterized. UOK257 cells harbor a cytosine insertion in a C tract, the frequently mutated hot spot inside exon 11 of FLCN, and have misplaced the wild form copy of FLCN. Cytogenetic analysis uncovered the cell line was nearly triploid displaying various unbal anced translocations and deletions of chromosomes. The MYC copy number was heterogeneous in UOK257 cells ranging from three to five copies. These you can look here cells formed tumors in immunodeficient mice exhibiting predomi nantly atypical clear epithelial cell sort histology, also as a variety of other histologic varieties which includes tubular papillary, and foci reminiscent of chromophobe RCC, all of which resemble the histologies inside of the tumor from which the cell line was derived.
Within the recent review, so as to investigate the tumor suppressor perform of FLCN we have now introduced wild form FLCN into UOK257 cells and in contrast their development in vitro and

in vivo. We noticed that wild variety FLCN suppressed tumor cell development in vivo, confirming the tumor suppressor function of FLCN. Moreover, we employed gene expression microarray examination to recognize novel downstream target genes of FLCN. Amid the dif ferentially expressed genes, we identified many vital genes associated with TGF B signaling like TGFB2, INHBA, THBS1, GREM1 and SMAD3. Because deregula tion of TGF B signaling is important in tumorigenesis and tumor progression, we characterized the expression of these genes in FLCN null and FLCN expressing cul tured cells likewise as in renal tumors surgically removed from BHD patients.