Box 7.

Erythroid 2-related Factor 2 (Nrf2).

Nrf2 is a transcription factor that is a major regulator of antioxidant defense in cells by checking intracellular levels of ROS and other oxidants. Nrf2 is continuously expressed in cells and at low oxidant levels rapidly ubiquitinated and proteosomally degraded. Nrf2 senses cellular oxidant levels by the oxidation rate of cysteine thiols. When the rate becomes too high, Nrf2 becomes stabilized 133 in a similar way as HIF1α and HIF2α expression is regulated. Nrf2 promotes transcription of genes that are involved in the formation of reduced glutathione, ROS detoxification, and degradation of xenobiotics,138,139 and Nrf2 induces the activity of NADPH-producing dehydrogenases and activates HIFs.140,141 NADPH is a major substrate for cellular detoxifying enzyme systems.27,47 Nrf2 activity is important for HSCs, HPCs, and HSPCs, but it may also be beneficial for cancer cells in relation to therapy resistance. On the other hand, Nrf2 knockout mice are more susceptible to develop cancer. 133 Therefore, it can be concluded that under normal conditions, Nrf2 protects against ROS damage, whereas in CSCs, Nrf2 is an important player in therapy resistance. 139

Abbreviations: ROS, reactive oxygen species; HIF, hypoxia-inducible factor; HSCs, hematopoietic stem cells; HPCs, hematopoietic progenitor cells; HSPCs, hematopoietic stem and progenitor cells; CSCs, cancer stem cells.