Figure 7.

Proposed mechanism for CXCL12-stimulated Nrf2-ARE-mediated CAT transcription. The two upper panels describe the differences between the regulatory mechanisms that support constitutive CAT expression in wt and #1 cells (left and right panels, respectively). The lower panels describe the potential mechanisms in oxidative stress, after exposure of wt and #1 cells (left and right panels, respectively) to H₂O₂. Under basal conditions (upper panels), Keap1 targets Nrf2 for ubiquitin-dependent degradation and in this way represses Nrf2-dependent gene expression. In #1 cells (upper right panel), CXCL12 binding to its receptor CXCR4 activates protein kinases (p38, Akt and ERK) and Nrf2 phosphorylation, inducing nuclear translocation of Nrf2 to a greater extent than in wt cells where the kinase activities are considerably lower. Consequently, in CXCL12-overexpressing #1 cells, more activated nuclear Nrf2 binds to the CAT gene promoter and maintains higher levels of CAT expression and enzymatic activity than in wt cells. After exposure to H₂O₂ (lower left panel), transient induction of p38, Akt and ERK kinases in wt cells was not accompanied by Nrf2 activation. The absence of Nrf2 activation could be attributed to the inhibitory effect of NFκB-p65 which was more abundant in the cytosol of wt than #1 cells after H₂O₂ treatment. By interacting with Keap1, NFκB-p65 represses Nrf2 dissociation from Keap1 and suppresses the Nrf2-ARE pathway.⁶⁴⁾ In #1 cells (lower right panel), the CXCL12 driven increase in nuclear translocation of Nrf2 remained after the H₂O₂ treatment probably because of high kinase activity. Nuclear translocation of Nrf2 was not disrupted by the redox-sensitive factor NFκB-p65. This is probably because of efficient H₂O₂ elimination in #1 cells as a result of the much higher level of basal CAT activity, which results in a lower level of oxidative stress.