ATF7
Cyclic AMP-dependent transcription factor ATF-7 (cAMP-dependent transcription factor ATF-7) (Activating transcription factor 7) (Transcription factor ATF-A) [ATFA]
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Cellular senescence plays an important role in aging and is induced by cyclin-dependent kinase (Cdk) inhibitors that accumulate following stresses during aging. However, the underlying mechanism remains elusive. Herein, we demonstrate that activating transcription factor 7 (ATF7), the stress-responsive recruiter of histone H3K9 di- and trimethyltransferases, functions in the accumulation of Cdk inhibitors. Atf7-deficient (Atf7 ) mice have a shorter lifespan than wild-type (WT) mice. Levels of p16 Cdk inhibitor mRNA increased with age more rapidly in Atf7 mice than in WT animals. ATF7 binds to the p16 gene promoter and was released with age. Consistently, histone H3K9me2 levels on the p16 gene promoter were lower in Atf7 mice than in WT animals. Similar results were obtained when Atf7 and WT mouse embryonic fibroblasts (MEFs) were cultured under 20% oxygen conditions, which induces cellular senescence via oxidative stress. Phosphorylation of ATF7 by p38 was also increased with the passage of MEFs, consistent with previous observations that ATF7 phosphorylation by p38 induces its release from chromatin. These results indicate that stress-induced and ATF7-dependent epigenetic changes on p16 genes play an important role in cellular senescence.
MeSH Terms
- Activating Transcription Factors
- Animals
- Cells, Cultured
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Epigenesis, Genetic
- Female
- Histones
- Longevity
- Male
- Mice
- Mice, Inbred C57BL
- Oxidative Stress
- Promoter Regions, Genetic
- Protein Binding
- p38 Mitogen-Activated Protein Kinases
Keywords
- cellular senescence
- histone H3K9me2
- lifespan
- stress
- transcription factor 7
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.
MeSH Terms
- Activating Transcription Factors
- Animals
- Animals, Genetically Modified
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Gene Expression Regulation
- HEK293 Cells
- Humans
- Insulin
- Longevity
- Metallothionein
- Mutagenesis
- Phosphorylation
- Protein-Serine-Threonine Kinases
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase
- Reactive Oxygen Species
- Signal Transduction