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Figure 2. Keap1-Nrf2 signaling pathway in cancer drug resistance. Interaction of Keap1 molecules to Nrf2 protein is followed by Cul3-based E3 ligase complex mediated Nrf2 polyubiquitylation results into its proteasomal degradation. In the absence of Keap1 molecules, Nrf2 freely enters in the nucleus and transcribes its target genes in association with other nuclear factors. PI3K/Akt/TNF-α/NF-κB pathway directly phosphorylates FOXO3a proteins and directs them for ubiquitination and proteasomal degradation. Normally, FOXO3a proteins inhibits FOXM1 function and represses FOXM1 targeted transcription. FOXO3a protein also transcribes Keap1 genes. Absence of FOXO3a protein results in to downregulation of Keap1mRNA and FOXM1 targeted genes