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A New Model for Raf Kinase Inhibitory Protein Induced Chemotherapeutic Resistance

Figure 8

A proposed model for RKIP-induced drug 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 [19], inactivation/ubiquitination of KEAP1 ensues. In addition, RKIP loss/depletion causes the inactivation of GSK3β through phosphorylation at its T390 residue by p38 [19]. Both events, ? which may be partly oxidative stress driven, culminate in the stabilization of NRF2 [30], [31], [32]. This consequently, enhances the transcription of antioxidants and phase II detoxification genes containing ARE-cis acting element culminating in the induction of drug resistance.

Figure 8