A New Model for Raf Kinase Inhibitory Protein Induced Chemotherapeutic Resistance
In unstressed normal cells and in the presence of abundant RKIP, NRF2 is kept in the cytoplasm by KEAP 1 binding and shuttled outside of the nucleus by GSK3β, phosphorylated FYN protein. Upon loss or the reduction of RKIP in a cell , inactivation/ubiquitination of KEAP1 ensues. In addition, RKIP loss/depletion causes the inactivation of GSK3β through phosphorylation at its T390 residue by p38 . Both events, ? which may be partly oxidative stress driven, culminate in the stabilization of NRF2 , , . This consequently, enhances the transcription of antioxidants and phase II detoxification genes containing ARE-cis acting element culminating in the induction of drug resistance.