AN IN SILICO ANALYSIS OF FOLLICULIN AND FOLLICULIN INTERACTING PROTEINS RESPONSIBLE FOR SKIN TUMORS AND BIRT HOGG DUBÉ SYNDROME.

Abstract

Birt–Hogg–Dube´ (BHD) syndrome is an inherited and autosomal disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from mutation in BHD gene / FLCN gene. The product of FLCN gene is folliculin protein which has been implicated in numerous signalling pathways like mTOR, AMPK signalling, HIF signalling, TGF-β signalling and the JAK-STAT signalling pathway. From literature it was clear that there were two major consequences of mutated folliculin. First is hindrance in formation of FLCN, FNIP1 and FNIP2 complex, which ultimately interacts with TGF-β protein of TGF-β signalling pathway and inactivates tumor suppression function of that pathway. The other major consequence is activation of HIF1A. From HIF-reporter cell-based screening studies of a natural product-like chemical library it is suggested that KC7F2 is an inhibitor of HIF1A. Thus here we have focused on another inducible factor HIF2A interaction with KC7F2 to carry out insilico analysis. A previous study also suggests ability of TSA to reverse the biological and molecular defects of BHD cells but they have also suggested that further work will be needed to elucidate the nature of these effects. So we have carried out the work to study the nature of these effects and the mode of interaction between TSA and TGF-β protein. We found that TSA binds with TGF-β protein at same site where the non-mutated folliculin protein was binding and thus the TGF-β protein works normally, as a result anti-proliferation will takes place via p15 protein and ultimately the tumor suppression will takes place.