Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf.

TitleCondition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf.
Publication TypeJournal Article
Year of Publication2009
AuthorsOliveira RP, Abate JPorter, Dilks K, Landis J, Ashraf J, Murphy CT, T Blackwell K
JournalAging Cell
Volume8
Issue5
Pagination524-41
Date Published2009 09
ISSN1474-9726
KeywordsAnimals, 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
Abstract

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.

DOI10.1111/j.1474-9726.2009.00501.x
Alternate JournalAging Cell
PubMed ID19575768
PubMed Central IDPMC2776707
Grant ListGM70088 / GM / NIGMS NIH HHS / United States
DK07260 / DK / NIDDK NIH HHS / United States
GM62891 / GM / NIGMS NIH HHS / United States
T32 DK007260 / DK / NIDDK NIH HHS / United States
F32 GM070088 / GM / NIGMS NIH HHS / United States
R01 GM062891-09 / GM / NIGMS NIH HHS / United States
R01 GM062891 / GM / NIGMS NIH HHS / United States