ATF3
Cyclic AMP-dependent transcription factor ATF-3 (cAMP-dependent transcription factor ATF-3) (Activating transcription factor 3)
Publications[править]
PINK1 (PTEN-induced putative kinase 1) is a key regulator of mitochondrial homeostasis that is relatively depleted in aging lungs and in lung epithelial cells from patients with idiopathic pulmonary fibrosis (IPF), a disease linked with aging. Impaired PINK1 expression and accumulation of damaged mitochondria in lung epithelial cells from fibrotic lungs were associated with the presence of ER stress. Here, we show that ATF3 (activating transcription factor 3), a member of the integrated stress response (ISR), negatively regulates transcription of the PINK1 gene. An ATF3 binding site within the human PINK1 promoter is located in the first 150 bp upstream of the transcription start site. Induction of ER stress or overexpression of ATF3 inhibited the activity of the PINK1 promoter. Importantly, overexpression of ATF3 causes accumulation of depolarized mitochondria, increased production of mitochondrial ROS, and loss of cell viability. Furthermore, conditional deletion of ATF3 in type II lung epithelial cells protects mice from bleomycin-induced lung fibrosis. Finally, we observed that ATF3 expression increases in the lung with age and, specially, in lung epithelial cells from IPF lungs. These data provide a unique link between ATF3 and PINK1 expression suggesting that persistent stress, driven by ATF3, can dysregulate mitochondrial homeostasis by repression of PINK1 mRNA synthesis.
MeSH Terms
- A549 Cells
- Activating Transcription Factor 3
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Alveolar Epithelial Cells
- Animals
- Bleomycin
- Endoplasmic Reticulum Stress
- Homeostasis
- Humans
- Mice
- Middle Aged
- Mitochondria
- Protein Kinases
- Pulmonary Fibrosis
- Transcription, Genetic
- Transfection
Keywords
- ER stress
- PTEN-induced putative kinase 1
- activating transcription factor 3
- aging
- idiopathic pulmonary fibrosis
- mitochondrial dysfunction
Persistent DNA damage induces profound alterations in gene expression that, in turn, influence tissue homeostasis, tumorigenesis, and cancer treatment outcome. However, the underlying mechanism for gene expression reprogramming induced by persistent DNA damage remains poorly understood. Here, using a highly effective bioluminescence-based reporter system and other tools, we report that persistent DNA damage inhibits nonsense-mediated RNA decay (NMD), an RNA surveillance and gene-regulatory pathway, in noncycling cells. NMD suppression by persistent DNA damage required the activity of the p38α MAPK. Activating transcription factor 3 (ATF3), an NMD target and a key stress-inducible transcription factor, was stabilized in a p38α- and NMD-dependent manner following persistent DNA damage. Our results reveal a novel p38α-dependent pathway that regulates NMD activity in response to persistent DNA damage, which, in turn, controls ATF3 expression in affected cells.
MeSH Terms
- Activating Transcription Factor 3
- Biomarkers
- Bleomycin
- Cells, Cultured
- Cellular Senescence
- DNA Damage
- Enzyme Activation
- Gamma Rays
- Gene Expression Regulation
- Genes, Reporter
- HEK293 Cells
- Humans
- Luminescent Measurements
- Mitogen-Activated Protein Kinase 14
- Mutagens
- Nonsense Mediated mRNA Decay
- Oxidative Stress
- Protein Stability
- RNA Interference
- RNA Stability
- RNA, Messenger
Keywords
- ATF3
- DNA damage response
- gene expression
- mRNA decay
- nonsense-mediated RNA decay
- p38
- persistent DNA damage
- senescence
A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1. Once in the nucleus, MGRN1 potentiates the transcriptional cellular response to proteotoxic stress. Inhibition of MGRN1 impairs ATF3-mediated neuronal responsiveness to proteosomal stress and increases neuronal stress, while increasing MGRN1 ameliorates signs of neuronal aging, including cognitive performance in old animals. Our results imply that, among others, the strength of neuronal survival in a proteasomal deterioration background, like during aging, depends on the fine-tuning of ubiquitination-deubiquitination.
MeSH Terms
- Activating Transcription Factor 3
- Active Transport, Cell Nucleus
- Aging
- Animals
- Behavior, Animal
- Cell Nucleus
- Cell Survival
- Chromatin
- Cognition
- Cytoplasm
- HEK293 Cells
- Hippocampus
- Humans
- Maze Learning
- Mice, Inbred C57BL
- Neurons
- Proteasome Endopeptidase Complex
- RNA Interference
- Rats, Wistar
- Signal Transduction
- Stress, Physiological
- Transcription, Genetic
- Transfection
- Ubiquitin
- Ubiquitin-Protein Ligases
- Ubiquitination
Keywords
- ATF3
- aging
- hippocampus
- mahogunin
- neuron
- proteasome
- stress response
- survival
- ubiquitin
Aging is a complex process which is accompanied by multiple related chronic diseases. Among them, metabolic dysfunction is one of the most important aging-related disorders. In the present study, we aimed to investigate the effect of rutin on aging-related metabolic dysfunction. We found that the increase of fasting blood glucose, insulin levels, blood pressure and HOMA-IR in aged rats was significantly inhibited by rutin. In addition, rutin improved glucose and insulin tolerance in aged rats, as reflected by decreased glucose level in IPGTT and IPITT test. Rutin treatment notably increased Akt and IRS-1 phosphorylation in the livers of old rats. The increase of inflammatory markers, such as IL-1β and TNFα, was prevented by the rutin administration. Moreover, in circulation and livers of old rats, rutin treatment significantly decreased the content of TG. Rutin also inhibited the increase of serum AST and ALT levels. Furthermore, rutin treatment markedly inhibited aging-related mitochondrial dysfunction, ER stress, and oxidative stress, as evidenced by increased oxygen consumption rate and activities of Na( )/K( )-ATPase and Ca2( )-ATPase, decreased expression of ATF3 and GRP78, decreased level of MDA, increased content of GSH and enhanced activity of SOD in aged rats. We show that the administration of rutin could effectively improve aging-related metabolic dysfunction. The amelioration of inflammation, lipid accumulation, mitochondrial dysfunction, ER stress, and oxidative stress may be involved in the effect of rutin on aging-related metabolic dysfunction. These findings provide novel insights into the potential use of rutin in the intervention of aging and its related metabolic diseases.
MeSH Terms
- Aging
- Animals
- Blood Pressure
- Endoplasmic Reticulum Stress
- Glucose Tolerance Test
- Inflammation
- Insulin
- Lipid Metabolism
- Liver
- Male
- Metabolic Diseases
- Mitochondria
- Oxidative Stress
- Protective Agents
- Rats
- Rats, Sprague-Dawley
- Rutin
Prior studies of aging and neuropathic injury have focused on senescent animals compared to young adults, while changes in middle age, particularly in the dorsal root ganglia (DRG), have remained largely unexplored. 14 neuroimmune mRNA markers, previously associated with peripheral nerve injury, were measured in multiplex assays of lumbar spinal cord (LSC), and DRG from young and middle-aged (3, 17 month) naïve rats, or from rats subjected to chronic constriction injury (CCI) of the sciatic nerve (after 7 days), or from aged-matched sham controls. Results showed that CD2, CD3e, CD68, CD45, TNF-α, IL6, CCL2, ATF3 and TGFβ1 mRNA levels were substantially elevated in LSC from naïve middle-aged animals compared to young adults. Similarly, LSC samples from older sham animals showed increased levels of T-cell and microglial/macrophage markers. CCI induced further increases in CCL2, and IL6, and elevated ATF3 mRNA levels in LSC of young and middle-aged adults. Immunofluorescence images of dorsal horn microglia from middle-aged naïve or sham rats were typically hypertrophic with mostly thickened, de-ramified processes, similar to microglia following CCI. Unlike the spinal cord, marker expression profiles in naïve DRG were unchanged across age (except increased ATF3); whereas, levels of GFAP protein, localized to satellite glia, were highly elevated in middle age, but independent of nerve injury. Most neuroimmune markers were elevated in DRG following CCI in young adults, yet middle-aged animals showed little response to injury. No age-related changes in nociception (heat, cold, mechanical) were observed in naïve adults, or at days 3 or 7 post-CCI. The patterns of marker expression and microglial morphologies in healthy middle age are consistent with development of a para-inflammatory state involving microglial activation and T-cell marker elevation in the dorsal horn, and neuronal stress and satellite cell activation in the DRG. These changes, however, did not affect the establishment of neuropathic pain.
MeSH Terms
- Age Factors
- Aging
- Animals
- Antigens, CD
- Cytokines
- Ganglia, Spinal
- Male
- Microglia
- Neuralgia
- Nociception
- Rats
- Satellite Cells, Perineuronal
- Sciatic Neuropathy
- Spinal Cord
Cutaneous squamous cell carcinoma (SCC) is a very common resectable cancer; however, cutaneous SCC is highly resistant to chemotherapy if metastasis develops. Activating transcription factor 3 (ATF3) has been suggested as a marker of advanced or metastatic cutaneous SCC. Autophagy is one of the most important mechanisms in cancer biology and commonly induced by in vitro serum starvation. To investigate the role of autophagy activation in cutaneous SCC, we activated autophagic pathways by serum starvation in SCC13 and ATF3-overexpressing SCC13 (ATF3-SCC13) cell lines. ATF3-SCC13 cells demonstrated high proliferative capacity and low p53 and autophagy levels in comparison with control SCC13 cells under basal conditions. Intriguingly, autophagic stimulation via serum starvation resulted in growth inhibition and senescence in both cells, while ATF3-SCC13 cells further demonstrated growth inhibition and senescence. Apoptosis was not significantly induced by autophagy activation. Taken together, autophagy activation may be a promising antitumor approach for advanced cutaneous SCC.
MeSH Terms
- Activating Transcription Factor 3
- Aged
- Aged, 80 and over
- Apoptosis
- Autophagy
- Biomarkers, Tumor
- Carcinoma, Squamous Cell
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Culture Media, Serum-Free
- Female
- Humans
- Male
- Middle Aged
- Signal Transduction
- Skin Neoplasms
- Tumor Suppressor Protein p53
Keywords
- activating transcription factor 3
- autophagy
- cutaneous squamous cell carcinoma
- growth inhibition
- senescence
The detrimental effect of activation of the chemokine CCL4/MIP-1β on neuronal integrity in patients with HIV-associated dementia has directed attention to the potential role of CCL4 expression and regulation in Alzheimer disease. Here, we show that CCL4 mRNA and protein are overexpressed in the brains of APPswe/PS1ΔE9 (APP/PS1) double-transgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from nontransgenic littermates or single-mutant controls. Increased levels of CCL4 mRNA and protein directly correlated with the age-related progression of cerebral amyloid-β (Aβ) levels in APP/PS1 mice. We also found significantly increased expression of activating transcription factor 3 (ATF3), which was positively correlated with age-related Aβ deposition and CCL4 in the brains of APP/PS1 mice. Results from chromatin immunoprecipitation-quantitative polymerase chain reaction confirmed that ATF3 binds to the promoter region of the CCL4 gene, consistent with a potential role in regulating CCL4 transcription. Finally, elevated ATF3 mRNA expression in APP/PS1 brains was associated with hypomethylation of the ATF3 gene promoter region. These observations prompt the testable hypothesis for future study that CCL4 overexpression, regulated in part by hypomethylation of the ATF3 gene, may contribute to neuropathologic progression associated with amyloid deposition in Alzheimer disease.
MeSH Terms
- Activating Transcription Factor 3
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Animals
- Brain
- Chemokine CCL4
- Chromatin Immunoprecipitation
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Gene Expression Regulation
- Glial Fibrillary Acidic Protein
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Mutation
- Presenilin-1
Degeneration of motor neurons contributes to senescence-associated loss of muscle function and underlies human neurodegenerative conditions such as amyotrophic lateral sclerosis and spinal muscular atrophy. The identification of genetic factors contributing to motor neuron vulnerability and degenerative phenotypes in vivo are therefore important for our understanding of the neuromuscular system in health and disease. Here, we analyzed neurodegenerative abnormalities in the spinal cord of progeroid Ercc1(Delta/-) mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair, and double strand break repair. Ercc1(Delta/-) mice develop age-dependent motor abnormalities, and have a shortened life span of 6-7 months. Pathologically, Ercc1(Delta/-) mice develop widespread astrocytosis and microgliosis, and motor neuron loss and denervation of skeletal muscle fibers. Degenerating motor neurons in many occasions expressed genotoxic-responsive transcription factors p53 or ATF3, and in addition, displayed a range of Golgi apparatus abnormalities. Furthermore, Ercc1(Delta/-) motor neurons developed perikaryal and axonal intermediate filament abnormalities reminiscent of cytoskeletal pathology observed in aging spinal cord. Our findings support the notion that accumulation of DNA damage and genotoxic stress may contribute to neuronal aging and motor neuron vulnerability in human neuromuscular disorders.
MeSH Terms
- Activating Transcription Factor 3
- Aging
- Animals
- Body Weight
- Bungarotoxins
- DNA-Binding Proteins
- Endonucleases
- Galectin 3
- Gene Expression Regulation
- Gliosis
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Motor Neurons
- Muscle Strength
- Nerve Degeneration
- Nerve Tissue Proteins
- Neurofilament Proteins
- Neuromuscular Junction
- Reaction Time
- Silver Staining
- Spinal Cord
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by progressive motor neuron degeneration and muscle paralysis. Genetic evidence from man and mouse has indicated that mutations in the dynein/dynactin motor complex are correlated with motor neuron degeneration. In this study, we have generated transgenic mice with neuron-specific expression of Bicaudal D2 N-terminus (BICD2-N) to chronically impair dynein/dynactin function. Motor neurons expressing BICD2-N showed accumulation of dynein and dynactin in the cell body, Golgi fragmentation and several signs of impaired retrograde trafficking: the appearance of giant neurofilament swellings in the proximal axon, reduced retrograde labelling by tracer injected in the muscle and delayed expression of the injury transcription factor ATF3 after axon transection. Despite these abnormalities, BICD2-N mice did not develop signs of motor neuron degeneration and motor abnormalities. Interestingly, the BICD2-N transgene increased lifespan in 'low copy' SOD1-G93A ALS transgenic mice. Our findings indicate that impaired dynein/dynactin function can explain several pathological features observed in ALS patients, but may be beneficial in some forms of ALS.
MeSH Terms
- Amyotrophic Lateral Sclerosis
- Animals
- Biological Transport
- Carrier Proteins
- Cells, Cultured
- Disease Models, Animal
- Dynactin Complex
- Dyneins
- Female
- Gene Expression
- Golgi Apparatus
- Humans
- Life Expectancy
- Male
- Membrane Proteins
- Mice
- Mice, Transgenic
- Microtubule-Associated Proteins
- Motor Neurons
- Rats
- Superoxide Dismutase
- Superoxide Dismutase-1
- Survival
Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause hereditary sensory and autonomic neuropathy (type I) (HSAN1), an adult onset, autosomal dominant neuropathy. HSAN1 patients have reduced SPT activity. Expression of mutant SPTLC1 in yeast and mammalian cell cultures dominantly inhibits SPT activity. We created transgenic mouse lines that ubiquitously overexpress either wild-type (SPTLC1(WT)) or mutant SPTLC1 (SPTLC1(C133W)). We report here that SPTLC1(C133W) mice develop age-dependent weight loss and mild sensory and motor impairments. Aged SPTLC1(C133W) mice lose large myelinated axons in the ventral root of the spinal cord and demonstrate myelin thinning. There is also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers are preserved. In the dorsal root ganglia, IB4 staining is diminished, whereas expression of the injury-induced transcription factor ATF3 is increased. These mice represent a novel mouse model of peripheral neuropathy and confirm the link between mutant SPT and neuronal dysfunction.
MeSH Terms
- Aging
- Animals
- Axons
- Behavior, Animal
- CHO Cells
- Cricetinae
- Cricetulus
- Female
- Genes, Dominant
- Hereditary Sensory and Autonomic Neuropathies
- Male
- Mice
- Mice, Transgenic
- Mutation
- Pancreas, Exocrine
- Serine C-Palmitoyltransferase
- Transfection