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J. Biol. Chem., Vol. 278, Issue 10, 8135-8145, March 7, 2003
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From the Enzyme inducers such as
3H-1,2-dithiole-3-thione (D3T) enhance the
detoxication of environmental carcinogens and protect against neoplasia. The putative molecular sensor for inducers is Keap1, a
sulfhydryl-rich protein that sequesters the transcription factor Nrf2 in the cytoplasm. Expression of these detoxication enzymes is blunted in nrf2-deficient mice; moreover, these
mice are more sensitive to carcinogenesis, and the protective actions
of dithiolethiones are lost with nrf2 disruption.
Hepatic gene expression profiles were examined by oligonucleotide
microarray analysis in vehicle- or D3T-treated wild-type mice as well
as in nrf2 single and keap1-nrf2 double knockout mice to identify those genes regulated by the Keap1-Nrf2 pathway. Transcript levels of 292 genes were elevated in wild-type mice 24 h after treatment with D3T; 79% of these genes were induced in wild-type, but not
nrf2-deficient mice. These
nrf2-dependent, D3T-inducible genes
included known detoxication and antioxidative enzymes. Unexpected
clusters included genes for chaperones, protein trafficking,
ubiquitin/26 S proteasome subunits, and signaling molecules. Gene
expression patterns in keap1-nrf2 double knockout
mice were similar to those in nrf2-single knockout
mice. D3T also led to nrf2-dependent
repression of 31 genes at 24 h; principally genes related to
cholesterol/lipid biosynthesis. Collectively, D3T increases the
expression of genes through the Keap1-Nrf2 signaling pathway
that directly detoxify toxins and generate essential cofactors such as
glutathione and reducing equivalents. Induction of
nrf2-dependent genes involved in the
recognition and repair/removal of damaged proteins expands the role of
this pathway beyond primary control of electrophilic and oxidative
stresses into secondary protective actions that enhance cell survival.
Modulation of Gene Expression by Cancer Chemopreventive
Dithiolethiones through the Keap1-Nrf2 Pathway
IDENTIFICATION OF NOVEL GENE CLUSTERS FOR CELL SURVIVAL*
,§,¶
Department of Environmental Health Sciences,
Johns Hopkins University Bloomberg School of Public Health, Baltimore,
Maryland 21205 and the § Institute of Basic Medical Sciences
and Center for Tsukuba Advanced Research Alliance, University of
Tsukuba, Tennoudai, Tsukuba 305-8577, Japan
*
This work was supported by Grants CA39416 and CA94076 from
the National Institutes of Health and Center Grant ES 03819.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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