It has been proposed that aging results from the lifelong accumulation of intracellular damage via reactions with reactive oxygen species (ROS). Metallothioneins are conserved cysteine-rich proteins that function as efficient ROS scavengers and may affect longevity. To better understand mechanisms controlling metallothionein expression, the regulatory factors and pathways that controlled cadmium-inducible transcription of the C. elegans metallothionein gene, mtl-1, were identified. The transcription factor ATF-7 was identified in both ethylmethanesulfonate mutagenesis and candidate gene screens. PMK-1 and members of the insulin signaling pathway, PDK-1 and AKT-1/2, were also identified as mtl-1 regulators. Genetic and previous results support a model for the regulation of cadmium-inducible mtl-1 transcription based on the derepression of the constitutively active transcription factor ELT-2. In addition, knockdown of the mammalian homologs of PDK1 and ATF7 in HEK293 cells resulted in changes in metallothionein expression, suggesting that this pathway was evolutionarily conserved. The insulin signaling pathway is known to influence the aging process; however, various factors responsible for affecting the aging phenotype are unknown. Identification of portions of the insulin signaling pathway as regulators of metallothionein expression supports the hypothesis that longevity is affected by the expression of this efficient ROS scavenger.
Bibliographical noteFunding Information:
This research was supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01ES102045 and Z01ES102046). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank the following people for their assistance with this manuscript: Ginger Miley for the construction of the pmtl-1: :GFP strain; Rachel Goldsmith for assistance with fluorescence microscopy; Julie Rice for assistance with the COPAS Biosort; and Marjolein Smith and Sandra McBride (SRA International) for assistance with the statistical analysis. Nematode strains used in this work were provided by the Caenorhabditis Genetics Center.