Table 2.

Transcription factors that are activated as a genetic reprograming adaptive response to chronic exposure to ROS

Gene
NRF2	First-tier defense (The principle inducible defense against oxidative stress) Downregulation of ROS production by suppressing the expression of NOX4, IL-1B, IL-6, etc. Upregulation of serine synthesis which leads to the production of GSH
AP-1	Second-tier defense Induction of the genes that: (1) scavenge ROS; (2) synthesize GSH; and (3) suppress the level of free iron
NF-κB	Second-tier defense It not only regulates the expression of antioxidant genes but also the expression of pro-oxidant genes such as CYP2E1, NOX2, XOR, NOS2, COX2, ALOX5, and ALOX12
FOXO	Induction of the genes that (1) eliminate ROS; (2) improve the mitochondrial Redox; and (3) suppress free transition of metal ions
HIF1-α	Regulate the expression of the antioxidant genes under hypoxia By inducing the genes encoding for lactate dehydrogenase and pyruvate dehydrogenase kinase, the reactions shift from TCA in mitochondria to lactate production and, as a result, reduction of ROS production by mitochondria
PGC-1α	It can increase antioxidant capacity and decrease the production of ROS by mitochondria through mitochondrial biogenesis and also activate uncoupling proteins
HSF1	Induction of antioxidant gene and also induction of heat shock protein
TP53	Through regulation of various genes with a wide range of activity from scavenging ROS, supporting GSH, to the third-tier defense which is apoptosis Under mild oxidative stress: TP53 induces gene expression leading to adaptatio Under high oxidative stress: TP53 activates the pathways leading to apoptosis

ROS: Reactive oxygen species; GSH: glutathione; HIF: hypoxia-inducible factor; TCA: tricarboxylic acid cycle.