No abstract

Keap1/Nrf2 signaling defends organisms against the detrimental effects of oxidative stress and has been suggested to abate its consequences, including aging-associated diseases like neurodegeneration, chronic inflammation, and cancer. Nrf2 is a prominent target for drug discovery, and Nrf2-activating agents are in clinical trials for cancer chemoprevention. However, aberrant activation of Nrf2 by keap1 somatic mutations may contribute to carcinogenesis and promote resistance to chemotherapy. To evaluate potential functions of Keap1 and Nrf2 for organismal homeostasis, we characterized the pathway in Drosophila. We demonstrate that Keap1/Nrf2 signaling in the fruit fly is activated by oxidants, induces antioxidant and detoxification responses, and confers increased tolerance to oxidative stress. Importantly, keap1 loss-of-function mutations extend the lifespan of Drosophila males, supporting a role for Nrf2 signaling in the regulation of longevity. Interestingly, cancer chemopreventive drugs potently stimulate Drosophila Nrf2 activity, suggesting the fruit fly as an experimental system to identify and characterize such agents.

Cap'n'collar (Cnc) transcription factors are conserved in metazoans and have important developmental and homeostatic functions. The vertebrate Nrf1, Nrf2, and Nrf3, the Caenorhabditis elegans SKN-1, and the Drosophila CncC comprise a subgroup of Cnc factors that mediate adaptive responses to cellular stress. The most studied stress-activated Cnc factor is Nrf2, which orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In rodent models, signaling by Nrf2 defends against oxidative stress and aging-associated disorders, such as neurodegeneration, respiratory diseases, and cancer. In humans, polymorphisms that decrease Nrf2 abundance have been associated with various pathologies of the skin, respiratory system, and digestive tract. In addition to preventing disease in rodents and humans, Cnc factors have lifespan-extending and anti-aging functions in invertebrates. However, despite the pro-longevity and antioxidant roles of stress-activated Cnc factors, their activity paradoxically declines in aging model organisms and in humans suffering from progressing respiratory disease or neurodegeneration. We review the roles and regulation of stressactivated Cnc factors across species, present all reported instances in which their activity is paradoxically decreased in aging and disease, and discuss the possibility that the pharmacological restoration of Nrf2 signaling may be useful in the prevention and treatment of age-related diseases. The Cnc Family of Transcription FactorsCap'n'collar (Cnc) proteins are a family of basic leucine zipper transcription factors that are conserved in worms, insects, fish, birds, and mammals, including humans, but are not present in plants or fungi. They are defined by the presence of a conserved 43-amino acid Cnc domain located N-terminally to the DNA binding domain. Cnc transcription factors comprise the Caenorhabditis elegans SKN-1 (Skinhead family member 1) (1), the Drosophila Cnc (2), and four vertebrate counterparts--the p45 NFE2 (nuclear factor erythroid-derived 2) and the NFE2-related factors Nrf1, Nrf2 and Nrf3 (hereafter referred to as "the Nrfs") ( Fig. 1) (3-10). The related vertebrate transcription factors Bach1 (BTB and CNC homology 1) and Bach2 are characterized by the additional presence of a BTB (Broad complex, Tramtrack, Bric-a-brac) protein interaction domain (11). Most Cnc factors are transcriptional activators; however, Bach 1, Bach2, a naturally occurring truncated isoform of Nrf1, and a caspase-cleaved form of Nrf2 function as transcriptional repressors (11)(12)(13)(14)(15)(16). One study has suggested that Bach1 can activate transcription in erythroid cells (11).* Corresponding author gerasimos_sykiotis@urmc.rochester.edu Telephone: (617)-643-2807 Fax: (617)-726-5357. Competing interests:The authors declare no competing interests. NIH Public Access Author ManuscriptSci Signal. Author manuscript; available in PMC 2010 November 24. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptCnc pr...

Nuclear oncogene products have the potential to induce alterations in gene regulation leading to the genesis of cancer. The biochemical mechanisms by which nuclear oncoproteins act remain unknown. Recently, an oncogene, v-jun, was found to share homology with the DNA binding domain of a yeast transcription factor, GCN4. Furthermore, GCN4 and the phorbol ester-inducible enhancer binding protein, AP-1, recognize very similar DNA sequences. The human proto-oncogene c-jun has now been isolated, and the deduced amino acid sequence indicates more than 80 percent identity with v-jun. Expression of cloned c-jun in bacteria produced a protein with sequence-specific DNA binding properties identical to AP-1. Antibodies raised against two distinct peptides derived from v-jun reacted specifically with human AP-1. In addition, partial amino acid sequence of purified AP-1 revealed tryptic peptides in common with the c-jun protein. The structural and functional similarities between the c-jun product and the enhancer binding protein suggest that AP-1 may be encoded by c-jun. These findings demonstrate that the proto-oncogene product of c-jun interacts directly with specific target DNA sequences to regulate gene expression, and therefore it may now be possible to identify genes under the control of c-jun that affect cell growth and neoplasia.