关键词： ATF3   rSNPs   TFBS   Human   Etiology  

摘要： Three rSNPs (rs3125289, rs1877474 and rs11119982) in one intron of the activating transcription factor 3 (ATF3) gene have been significantly associated with the human etiology of hypospadias and may be associated with human disease. These rSNP alleles alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in transcriptional factor binding sites (TFBS). These TFBS changes are examined with respect to the human etiology of hypospadias which has been found to be significantly associated with the rSNPs.

关键词： Type 2 diabetes   Pancreatic beta-cells   ER stress   AMPK   ATF3   In vivo knockdown   ENDOPLASMIC-RETICULUM STRESS   CHRONIC HIGH GLUCOSE   PROTEIN-KINASE   GENE-EXPRESSION   OXIDATIVE STRESS   REGULATORY ROLE   METABOLISM   PATHWAY   PATHOGENESIS   APOPTOSIS  

摘要： In obese Zucker diabetic fatty (ZDF) rats, ER stress is associated with insulin resistance and pancreatic beta-cell dysfunction: however the exact mechanisms by which ER stress drives type-2 diabetes remain uncertain. Here, we investigated the role of ATF3 on the preventive regulation of AMPK against ER stress-mediated beta-cell dysfunction during the end-stage progression of hyperglycemia in ZDF rats. The impaired glucose metabolism and beta-cell dysfunction were significantly increased in late-diabetic phase 19-week-old ZDF rats. Although AMPK phosphorylation reduced in 6- and 12-week-old ZDF rats was remarkably increased at 19 weeks, the increases of lipogenice genes, ATF3, and ER stress or ROS-mediated beta-cell dysfunction were still remained, which were attenuated by in vivo-injection of chemical chaperon tauroursodeoxycholate (TUDCA), chronic AICAR, or antioxidants. ATF3 did not directly affect AMPK phosphorylation, but counteracts the preventive effects of AMPK for high glucose-induced beta-cell dysfunction. Moreover, knockdown of ATF3 by delivery of in vivo-jetPEI ATF3 siRNA attenuated ER stress-mediated beta-cell dysfunction and enhanced the beneficial effect of AICAR. Our data suggest that ATF3 may play as a counteracting regulator of AMPK and thus promote beta-cell dysfunction and the development of type-2 diabetes and could be a potential therapeutic target in treating type-2 diabetes. (C) 2013 Elsevier Inc. All rights reserved.

关键词： NF-KAPPA-B   ACTIVATING TRANSCRIPTION FACTOR-3   INFLAMMATORY-BOWEL-DISEASE   CHRONIC NOD2 STIMULATION   MURAMYL DIPEPTIDE   ENDOTOXIN TOLERANCE   NEGATIVE REGULATION   MEDIATES TOLERANCE   CROSS-TOLERANCE   MACROPHAGES  

摘要： Regulation of microbially induced cytokine secretion is critical in intestinal immune homeostasis. NOD2, the Crohn's diseaseassociated bacterial peptidoglycan sensor, activates the NF-kappa B pathway. After chronic NOD2 stimulation in human macrophages, cytokine secretion is significantly attenuated, similar to the situation in the intestinal environment. We find that NF-kappa B1 (p105/p50) expression is upregulated with chronic NOD2 stimulation and is required for attenuation of cytokine secretion in vitro in human macrophages and in vivo in mice. Upon chronic NOD2 stimulation, regulation of both activating (H3K4Me2 and H4Ac) and inhibitory (H3K27Me3) histone modifications was observed within cytokine gene promoters; these outcomes were NF-kappa B1 dependent. In addition to enhanced binding to cytokine gene promoters with chronic NOD2 stimulation, NF-kappa B1 bound to the promoter of the transcriptional repressor, ATF3. ATF3 was then induced and bound to cytokine gene promoters; both features were impaired upon NF-kappa B1 knockdown. Restoring ATF3 expression under NF-kappa B1 knockdown conditions restored NOD2-mediated cytokine downregulation. Finally, NF-kappa B1 and ATF3 cooperate with other inhibitory pathways, including IRAKM and secreted mediators, to downregulate cytokine secretion after chronic NOD2 stimulation. Therefore, we identify NF-kappa B1 and ATF3 as critical mechanisms through which NOD2 downregulates cytokines and contributes to intestinal immune homeostasis.

关键词： Chemotherapy-induced neuropathy   satellite cells   microglia   astrocytes   ATF3   neurofilament   ROOT GANGLION NEURONS   CINGULATE CORTEX   DIFFERENT SCHEDULES   1ST-LINE TREATMENT   ADJUVANT TREATMENT   OXIDATIVE STRESS   NERVOUS-SYSTEM   CISPLATIN   NEUROTOXICITY   CANCER  

摘要： Neurotoxicity is the limiting side effect of the anticancer agent oxaliplatin. A tangled panel of symptoms, sensory loss, paresthesia, dysesthesia, and pain may be disabling for patients and adversely affect their quality of life. To elucidate the morphologic and molecular alterations that occur in the nervous system during neuropathy, rats were daily injected with 2.4 mg kg(-1) oxaliplatin intraperitoneally. A progressive decrease in the pain threshold and hypersensitivity to noxious and nonnoxious stimuli were evidenced during the treatment (7, 14, 21 days). On day 21, morphometric alterations were detectable exclusively in the dorsal root ganglia, whereas the activating transcription factor 3 and neurofilament (heavy-chain) expression changed dramatically in both the nerves and ganglia. Inflammatory features were not highlighted. Interestingly, satellite cells exhibited signs of activation. Glial modulation was characterized in the spinal cord and brain areas involved in pain signaling. On the 21st day, spinal astrocytes increased numerically whereas the microglial population was unaltered. The number of glial cells in the brain differed according to the zone and treatment time points. In particular, on day 21, a significant astrocyte increase was measured in the anterior cingulate cortex, somatosensory area 1, neostriatum, ventrolateral periaqueductal gray, and nucleus raphe magnus. (C) 2013 by the American Pain Society

关键词： NF-KAPPA-B   ACTIVATING TRANSCRIPTION FACTOR-3   RIBOTOXIC STRESS-RESPONSE   NECROSIS-FACTOR-ALPHA   T-2 TOXIN   BINDING PROTEIN   MESSENGER-RNA   INFLAMMATORY RESPONSE   NEGATIVE REGULATOR   MURAMYL DIPEPTIDE  

摘要： In response to excessive nucleotide-binding oligomerization domain-containing protein 2 (Nod2) stimulation caused by mucosal bacterial components, gut epithelia need to activate regulatory machinery to maintain epithelial homeostasis. Activating transcription factor 3 (ATF3) is a representative regulator in the negative feedback loop that modulates TLR-associated inflammatory responses. In the current study, the regulatory effects of ribosomal stress-induced ATF3 on Nod2-stimulated proinflammatory signals were assessed. Ribosomal inactivation caused persistent ATF3 expression that in turn suppressed proinflammatory chemokine production facilitated by Nod2. Decreased chemokine production was due to attenuation of Nod2-activated NF-kappa B and early growth response protein 1 (EGR-1) signals by ATF3. However, the underlying molecular mechanisms involve two convergent regulatory pathways. Although ATF3 induced by ribosomal inactivation regulated Nod2-induced EGR-1 expression epigenetically through the recruitment of histone deacetylase 1, NF-kappa B regulation was associated with posttranscriptional regulation by ATF3 rather than epigenetic modification. ATF3 induced by ribosomal inactivation led to the destabilization of p65 mRNA caused by nuclear entrapment of transcript-stabilizing human Ag R protein via direct interaction with ATF3. These findings demonstrate that ribosomal stress-induced ATF3 is a critical regulator in the convergent pathways between EGR-1 and NF-kappa B, which contributes to the suppression of Nod2-activated proinflammatory gene expression.

关键词： ACTIVATING TRANSCRIPTION FACTOR-3   ADAPTIVE-RESPONSE GENE   NF-KAPPA-B   TYROSINE-KINASE   STRESS-RESPONSE   NEGATIVE REGULATOR   EPITHELIAL-CELLS   RESISTANCE   GONOCOCCI   CANCER  

摘要： Neisseria gonorrhoeae regulates the expression of epithelial cell genes, activates cytoprotective pathways in the infected cell and protects it from apoptosis. Many of these responses are enhanced by the Type IV pilus (Tfp). We tested the hypothesis that *** modulates the innate immune response by inducing expression of ATF3, a transcription factor that negatively regulates the expression of many cytokine genes. We further determined whether Tfp are involved in these events. We found that *** induces ATF3 expression in mucosal epithelial cells through activation of mitogen-activated protein kinases. Maximal ATF3 expression requires Tfp retraction. Knocking down endogenous levels of ATF3 results in higher levels of IL-6 transcript. Our findings strongly suggest that ATF3 is involved in suppressing cytokine expression during gonococcal infection. We propose a model for the role of ATF3 in the context of *** infection.

关键词： Integrated stress response   ATF3   Cuprizone   Amino acid   MULTIPLE-SCLEROSIS LESIONS   CENTRAL-NERVOUS-SYSTEM   INDUCED DEMYELINATION   COPPER DEFICIENCY   GENE-EXPRESSION   TRANSCRIPTION FACTOR-3   SUPEROXIDE-DISMUTASE   STATUS SPONGIOSUS   CORPUS-CALLOSUM   MOUSE-LIVER  

摘要： Cuprizone [bis(cyclohexylidenehydrazide)]-induced toxic demyelination is an experimental approach frequently used to study de- and re-myelination in the central nervous system. In this model, mice are fed with the copper chelator cuprizone which leads to oligodendrocyte apoptosis and subsequent microgliosis, astrocytosis, and demyelination. The underlying mechanisms of cuprizone-induced oligodendrocyte death are still unknown. We analysed differences in amino acid levels after short-term cuprizone exposure (i.e., 4 days). Furthermore, an amino acid response (AAR) pathway activated in oligodendrocytes after cuprizone intoxication was evaluated. Short-term cuprizone exposure resulted in a selective decrease of alanine, glycine, and proline plasma levels, which was paralleled by an increase of apoptotic cells in the liver and a decrease of alanine aminotransferase in the serum. These parameters were paralleled by oligodendrocyte apoptosis and the induction of an AAR with increased expression of the transcription factors ATF-3 and ATF-4 (activating transcription factor-3 and -4). Immunohistochemistry revealed that ATF-3 is exclusively expressed by oligodendrocytes and localized to the nuclear compartment. Our results suggest that cuprizone-induced liver dysfunction results in amino acid starvation and in consequence to the activation of an AAR. We propose that this stress response modulates oligodendrocyte viability in the cuprizone animal model.

关键词： Activating transcription factor 3 (ATF3)   Breast cancer   Clinical significance   Immunohistochemistry   Prognostic indicator   ADAPTIVE-RESPONSE GENE   ATF3  

摘要： Objective(s): Breast cancer is the most common type of cancer among women worldwide. This study investigated the expression and clinical significance of activating transcription factor 3 (ATF3) in human breast cancer and its relationship with the clinical outcome of breast cancer. Materials and Methods: ATF3 expressions were detected in 114 primary breast cancer tissues and 114 adjacent normal tissues using immunohistochemistry (IHC) assay. Categorical variables were statistically compared by chi-square or Fisher's exact test. Survival curves were evaluated using the Kaplan-Meier method and comparisons of survival rates were tested using a Log-rank test. Results: IHC analysis showed that the positive expression of ATF3 protein was detected in breast cancer tissue with a positive ratio of 76.3%, and the positive ATF3 expression in adjacent normal breast tissue was 13.2%, which is lower than that in breast cancer tissue samples (P<0.01). Furthermore, ATF3 expression showed significant correlation with TNM stage, invasion, lymph node metastasis and number of metastatic lymph nodes (P=0.038, P=0.029, P=0.026, and P=0.039 respectively), and did not correlate with patients' age and tumor size (P>0.05). A significant difference in overall survival rate was found between the patients with positive expression of ATF3 protein and those with negative expression (P=0.041). Conclusion: Increased ATF3 expression participate in the tumorigenesis, invasion and metastasis of breast cancer, and ATF3 may be useful as a new prognostic indicator for breast cancer patients.

关键词： HYDROGEN sulfide   POISONOUS gases   LUNGS   WOUNDS & injuries   REFRIGERANTS  

摘要： Rational Our group has recently shown that inhalation of hydrogen sulfide (H 2 S) during mechanical ventilation protects against VILI [1] . Here we explored the gene expression profile of this model in order to identify underlying molecular mechanisms. Methods C57/BL6 mice were randomized into four groups ( n   =   5/group). Two groups of control animals were breathing spontaneously air with or without H 2 S (80   ppm). Two groups were ventilated with synthetic air with or without H 2 S as described previously [1] . Lung injury was assessed by an acute lung injury scoring system in hematoxylin and eosin (H& E) stained tissue sections. Bronchoalveolar lavage fluid (BALF) was analysed for inflammatory infiltration. Micro array analysis was performed with RNA from lung tissue samples. Genes with different expression (ANOVA p   ⩽   0.05; fold induction or suppression ⩾2.2) were considered for further analysis. Gene expression of Atf3 was validated by sqPCR and Western Blot. The functional relevance of Atf3 up-regulation was validated in Atf3-Morpfolino knockout mice ventilated in presence of H 2 S. Results Mechanical ventilation led to lung injury, i . e ., H& E-stained samples revealed clear thickening of alveolar walls and increased amounts of inflammatory cell infiltrates in lung sections and BALF from animals ventilated with synthetic air. In contrast, the presence of H 2 S prevented lung injury as well as neutrophil and macrophage infiltration. Spontaneous breathing control animals regardless of the presence or absence of H 2 S showed no significant effects on lung injury or inflammation. H 2 S application led to differential expression of 137 genes. Among these, Atf3 was chosen for further analysis. In contrast to the protective effects of H 2 S in ventilated mice, Atf3-Morpholino mice developed despite the presence of H 2 S sings of lung injury, i . e ., enlarged alveolar walls, increased inflammatory cell infiltrates, and occurrence of sporadic blood vessel leak

关键词： NNZ-2566   Penetrating ballistic-like brain injury   Traumatic brain injury   TRAUMATIC BRAIN-INJURY   NATURAL-KILLER-CELLS   GLY-PRO-GLU   RAT MODEL   IN-VIVO   GLYPROMATE ANALOG   NERVOUS-SYSTEM   EXPRESSION   ASTROCYTES   ENCEPHALOMYELITIS  

摘要： The tripeptide glycine-proline-glutamate analogue NNZ-2566 (Neuren Pharmaceuticals) demonstrates neuroprotective efficacy in models of traumatic brain injury. In penetrating ballistic-like brain injury (PBBI), it significantly decreases injury-induced upregulation of inflammatory cytokines including TNF-alpha, IFN-gamma, and IL-6. However, the mechanism by which NNZ-2566 acts has yet to be determined. The activating transcription factor-3 (ATF3) is known to repress expression of these inflammatory cytokines and was increased at the mRNA and protein level 24-h post-PBBI. This study investigated whether 12 h of NNZ-2566 treatment following PBBI alters atf3 expression. PBBI alone significantly increased atf3 mRNA levels by 13-fold at 12 h and these levels were increased by an additional fourfold with NNZ-2566 treatment. To confirm that changes in mRNA translated to changes in protein expression, ATF3 expression levels were determined in vivo in microglia/macrophages, T cells, natural killer cells (NKCs), astrocytes, and neurons. PBBI alone significantly increased ATF3 in microglia/macrophages (820 %), NKCs (58 %), and astrocytes (51 %), but decreased levels in T cells (48 %). NNZ-2566 treatment further increased ATF3 protein expression in microglia/macrophages (102 %), NKCs (308 %), and astrocytes (13 %), while reversing ATF3 decreases in T cells. Finally, PBBI increased ATF3 levels by 55 % in neurons and NNZ-2566 treatment further increased these levels an additional 33 %. Since increased ATF3 may be an innate protective mechanism to limit inflammation following injury, these results demonstrating that the anti-inflammatory and neuroprotective drug NNZ-2566 increase both mRNA and protein levels of ATF3 in multiple cell types provide a cellular mechanism for NNZ-2566 modulation of neuroinflammation following PBBI.