Редактирование: ATF3

Cyclic AMP-dependent transcription factor ATF-3 (cAMP-dependent transcription factor ATF-3) (Activating transcription factor 3)

==Publications==

{{medline-entry
|title=[[ATF3]] represses [[PINK1]] gene transcription in lung epithelial cells to control mitochondrial homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29363258
|abstract=[[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
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847866
}}
{{medline-entry
|title=p38 MAPK inhibits nonsense-mediated RNA decay in response to persistent DNA damage in noncycling cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28765281
|abstract=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
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602387
}}
{{medline-entry
|title=Aging Triggers Cytoplasmic Depletion and Nuclear Translocation of the E3 Ligase Mahogunin: A Function for Ubiquitin in Neuronal Survival.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28475871
|abstract=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
|full-text-url=https://sci-hub.do/10.1016/j.molcel.2017.04.005
}}
{{medline-entry
|title=Rutin protects against aging-related metabolic dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26804783
|abstract=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

|full-text-url=https://sci-hub.do/10.1039/c5fo01036e
}}
{{medline-entry
|title=Neuroimmune and Neuropathic Responses of Spinal Cord and Dorsal Root Ganglia in Middle Age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26241743
|abstract=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

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524632
}}
{{medline-entry
|title=Activation of autophagic pathways is related to growth inhibition and senescence in cutaneous squamous cell carcinoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25046976
|abstract=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
|full-text-url=https://sci-hub.do/10.1111/exd.12515
}}
{{medline-entry
|title=Age-related brain expression and regulation of the chemokine [[CCL4]]/MIP-1β in APP/PS1 double-transgenic mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24607962
|abstract=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

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977177
}}
{{medline-entry
|title=Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20602234
|abstract=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

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923326
}}
{{medline-entry
|title=A novel mouse model with impaired dynein/dynactin function develops amyotrophic lateral sclerosis (ALS)-like features in motor neurons and improves lifespan in [[SOD1]]-ALS mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18579581
|abstract=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

|full-text-url=https://sci-hub.do/10.1093/hmg/ddn182
}}
{{medline-entry
|title=Mutant [[SPTLC1]] dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/16210380
|abstract=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

|full-text-url=https://sci-hub.do/10.1093/hmg/ddi380
}}