|Title||Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf.|
|Publication Type||Journal Article|
|Year of Publication||2009|
|Authors||Oliveira, RP, Abate, JPorter, Dilks, K, Landis, J, Ashraf, J, Murphy, CT, T Blackwell, K|
|Date Published||2009 Sep|
|Keywords||Animals, Arsenites, Caenorhabditis elegans, Caenorhabditis elegans Proteins, DNA, Helminth, DNA-Binding Proteins, Down-Regulation, Gene Expression Regulation, Longevity, NF-E2-Related Factor 1, Oligonucleotide Array Sequence Analysis, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, RNA, Messenger, tert-Butylhydroperoxide, Transcription Factors, Transcription, Genetic|
Studies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In Caenorhabditis elegans, the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog of mammalian Nrf proteins, which induce Phase 2 detoxification genes in response to stress. Phase 2 enzymes defend against oxygen radicals and conjugate electrophiles that are produced by Phase 1 detoxification enzymes, which metabolize lipophilic compounds. Here, we have used expression profiling to identify genes and processes that are regulated by SKN-1 under normal and stress-response conditions. Under nonstressed conditions SKN-1 upregulates numerous genes involved in detoxification, cellular repair, and other functions, and downregulates a set of genes that reduce stress resistance and lifespan. Many of these genes appear to be direct SKN-1 targets, based upon presence of predicted SKN-binding sites in their promoters. The metalloid sodium arsenite induces skn-1-dependent activation of certain detoxification gene groups, including some that were not SKN-1-upregulated under normal conditions. An organic peroxide also triggers induction of a discrete Phase 2 gene set, but additionally stimulates a broad SKN-1-independent response. We conclude that under normal conditions SKN-1 has a wide range of functions in detoxification and other processes, including modulating mechanisms that reduce lifespan. In response to stress, SKN-1 and other regulators tailor transcription programs to meet the challenge at hand. Our findings reveal striking complexity in SKN-1 functions and the regulation of systemic detoxification defenses.
|Alternate Journal||Aging Cell|