The saga of leucine zippers continues: in response to oxidative stress.

Oxidative stress results from either overproduction of reactive oxygen species (ROS), attenuation of endogenous enzymatic and nonenzymatic antioxidant defense systems, or both. The cellular and molecular adaptive responses to oxidative stress involve increased expression of antioxidant enzymes, phase II detoxification enzymes, and stressinducible cytoprotective genes aimed at reversing the oxidant imbalance and achieving cellular homeostasis. The ability and efficacy of these adaptive responses to achieve and maintain redox homeostasis in large part dictate whether the cell or organ will survive the oxidant burden. Central to these adaptive responses are the activation of specific signal transduction pathways, which then regulate selective and specific induction of antioxidant and detoxifying enzymes, and cytoprotective genes to confer cytoprotective functions. A vital component of these signaling pathways are the critical role of transcription factors which regulate the coordinate induction of antioxidant enzymes and cytoprotective genes. Transcription factors represent the “key” to activating and regulating downstream effector genes which provide cytoprotection, and many of them are sensitive to changes in cellular redox state or oxidative stresses. The redox-sensitive transcription factors, nuclear factor (NF)B and activator protein (AP)-1, are two of the most prominent regulators of cellular responses to oxidative stress. The family of AP-1 transcription factors has attracted much attention for numerous investigators, as they play critical roles in regulating target genes involved not only in adaptive responses to oxidative stress, but also in the regulation of gene products involved in a plethora of biologic processes, including, but not limited to, inflammation, cell differentiation and proliferation, and cell death or apoptosis. AP-1 belongs to the family of basic region/leucine zipper (bZIP) transcription factors (1), which are characterized by a basic domain required for sequence-specific DNA binding activity and a region containing heptad repeats of leucine and hydrophobic residues required for dimerization to other bZIP protein family members. For instance, the “classic AP-1” family of transcriptional activators include Jun-Jun or Jun-Fos dimers, which bind to the 12-O tetradecanoylphorbol-13-acetate (TPA)-responsive element (TRE) consensus sequence TGAC/GTC/AA ( see Table 1). The classification of bZIP family of proteins became more complex by the discovery of the antioxidant response element (ARE) in 1991 by Pickett and colleagues (2). The ARE is a unique cis -acting regulatory sequence found in the 5 regulatory region of genes encoding enzymes involved in the phase II metabolism of xenobiotics (2, 3). For example, phase II enzymes such as glutathione S -transferase (GST) Ya subunit genes and NAD(P)H:quinone oxidoreductase (NQO1) contain the ARE in the 5 upstream region, and induction of these enzymes resulting from cellular exposure to ROS is regulated by the activation of the ARE (2, 3). Pickett and colleagues suggested that the sequence 5 -GTGACNNNGC 3 , where N is any nucleotide, represents the core sequence of the ARE, is required for transcriptional activation by ROS, and may represent a major signaling pathway by which cells sense and respond to oxidative stress (Table 1). This ARE core sequence is similar to the sequence recognized by the “classic AP-1” family members, and many investigators hypothesized that members of the Jun and Fos families of transcription factors may be binding to the ARE sequence genes such as the GST and NQO1 genes. This hypothesis was supported by studies illustrating the induction of Jun and Fos in response to oxidative stress (1, 4). However, recent data clearly show that transcription factors distinct from the “classic AP-1” family members of Jun and Fos regulate transcriptional activation of the ARE. For example, several studies suggest that the transcription factor Nrf2 plays an important role in regulating ARE-mediated gene transcription (5–9). Nrf2 is a member of the “cap ‘n’ collar” family of bZIP transcription factors (CNC-bZIP), highly homologous to the NF-E2 transcription factors (10– 12). Transcription factor NF-E2 was originally identified as an erythroid cell-specific DNA binding protein which recognizes the consensus sequence TGCTGAG/CTCAT/C, which contains the TPA responsive element TGAG/CTCA, and exhibits high similarity to the consensus sequence of the ARE (12) (Table 1). Unlike the erythroid cell specific NF-E2, Nrf2 is expressed in a variety of tissues including the lung (10). Nrf1, another member of the CNC-bZIP family of transcription factors, is much less characterized to date. ( Received in original form December 27, 2001 )