关键词： apoptosis   endoplasmic reticulum stress   inclusion   motoneuron disease   programmed cell death   ALS-LINKED SOD1   ACTIVATING TRANSCRIPTION FACTOR-3   MOLECULAR-WEIGHT COMPLEXES   CU,ZN SUPEROXIDE-DISMUTASE   PROGRAMMED CELL-DEATH   MOUSE MODEL   MOTOR-NEURONS   DISEASE PROGRESSION   AXONAL-TRANSPORT   GENE-EXPRESSION  

摘要： To obtain insight into the morphological and molecular correlates of motoneuron degeneration in amyotrophic lateral sclerosis (ALS) mice that express G93A mutant superoxide dismutase (SOD)1 (G93A mice), we have mapped and characterized 'sick' motoneurons labelled by the 'stress transcription factors' ATF3 and phospho-c-Jun. Immunocytochemistry and in situ hybridization showed that a subset of motoneurons express ATF3 from a relatively early phase of disease before the onset of active caspase 3 expression and motoneuron loss. The highest number of ATF3-expressing motoneurons occurred at symptom onset. The onset of ATF3 expression correlated with the appearance of ubiquitinated neurites. Confocal double-labelling immunofluorescence showed that all ATF3-positive motoneurons were immunoreactive for phosphorylated c-Jun. Furthermore, the majority of ATF3 and phospho-c-Jun-positive motoneurons were also immunoreactive for CHOP (GADD153) and showed Golgi fragmentation. A subset of ATF3 and phosphorylated c-Jun-immunoreactive motoneurons showed an abnormal appearance characterized by a number of distinctive features, including an eccentric flattened nucleus, perikaryal accumulation of ubiquitin immunoreactivity, juxta-nuclear accumulation of the Golgi apparatus and the endoplasmic reticulum, and intense Hsp70 immunoreactivity. These abnormal cells were not immunoreactive for active caspase 3. We conclude that motoneurons in ALS-SOD1 mice prior to their death and disappearance experience a prolonged sick phase, characterized by the gradual accumulation of ubiquitinated material first in the neurites and subsequently the cell body.

关键词： V. parahaemolyticus   TDH   TTSS   apoptosis   Microarray   Egr   ATF3   Gadd34   TRANSCRIPTION FACTOR   SECRETION SYSTEMS   STRESS-RESPONSE   GROWTH ARREST   ENTEROTOXICITY   CYTOTOXICITY   ACTIVATION   GADD34   DEATH   LINE  

摘要： The thermostable direct hemolysin (TDH) is considered as a major virulence factor of Vibrio parahaemolyticus. We observed this potential in several human cancer cell lines by using the TDH-producing wild-type (RIMD2210633) as well as tdh-deletion mutant of V. parahaemolyticus and found that the deletion of tdh did not affect cytotoxicity to any of the cell lines tested. DNA fragmentation and annexin V staining showed that both wild-type and tdh-mutant trigger apoptosis in these cells. To understand the molecular basis of cell death in the absence of TDH, gene expression profile of human colon cancer cell line HCT116 infected with tdh-deletion mutant was carried out using human cDNA microarrays consisting of 33,000 known genes. In infected cells, differentially expressed genes including genes for early growth response, growth arrest and DNA damage, and activating transcription factor that affect programmed cell death pathways were detected. Interestingly, mutant strains having a deletion in type 111 secretion system 1 (TTSS1) failed to elicit DNA fragmentation in HCT1 16 cells. Our results strongly suggest that apoptosis requires functional TTSS1 and TTSS1-dependent translocation factor(s) to be associated with the host cell death, and thus pathogenesis of V. parahaemolyticus. (c) 2005 Elsevier Inc. All rights reserved.

摘要： Measured ATF3 jet noise is analyzed and compared with that of a small turbojet and turbofan operating at comparable engine conditions. Shown by the data/analysis is (1) the ATF3's absence of the dramatic lobing of jet noise energy characteristic of other jet engines, (2) ATF3 jet noise levels 24 dB and 31 dB lower than the turbofan and turbojet, respectively, for operation at comparable thrust, (3) ATF3 jet noise 8 dB lower than the turbofan for operation at comparable jet efflux velocity, and (4) a jet noise variance between engines of ten times the logarithm to the base ten of the product of the ratio of the primary jet efflux velocity raised to the sixth power and the ratio of the primary jet nozzle diameter raised to the third power; i.e., 10 log10[(V2/V1)6(D2/D1)3].

关键词： laminin 5   p38 MAPK   ATF3   epidermal wounds   VASCULAR ENDOTHELIAL-CELLS   MESSENGER-RNA STABILITY   EPITHELIAL-CELLS   PROTEIN-KINASE   CANCER CELLS   INTEGRIN ALPHA-3-BETA-1   GENE-EXPRESSION   HUMAN SKIN   3-DIMENSIONAL COLLAGEN   PLASMINOGEN-ACTIVATOR  

摘要： Quiescent epidermis anchors to laminin 5 in the basement membrane via integrin alpha 6 beta 4. Wounding elevates expression of laminin 5, generating leading keratinocytes (LKs) that migrate via beta 1 integrins. Laminin 5 was evaluated as a regulator of cell signaling, and mRNA and protein expression in LKs. An in vitro wound model was developed based on suspension and re-adhesion of quiescent human keratinocytes (HKs). DNA microarrays identified multiple mRNAs elevated 1.5 hours after suspension and re-adhesion including activation transcription factor 3 (ATF3). In vitro and in vivo, levels of ATF3 protein elevate in nuclei of LKs, but not in nuclei of the following cells, 2 hours after suspension or wounding but decline by 12-18 hours post injury. Significantly, null defects in laminin 5 or integrin beta 4 that inhibit anchorage chronically elevate ATF3 in vivo. This suggests that adhesion to laminin 5, but not other ligands, suppresses activation. On suspension, ATF3 and other transcripts in the microarrays are elevated by phosphorylated p38 mitogen-activated protein kinase (P-p38), a stress kinase that regulates mRNA and cell motility. Inhibition of P-p38 with 58203580 prevents phosphorylation of ATF2, a transcription factor for ATF3 in LKs. Re-adhesion to laminin 5 via alpha 6 beta 4 dephosphorylates P-p38 and suppresses ATF3 protein relative to cells in suspension. Thus, wounding of quiescent HKs disrupts laminin 5 adhesion to activate p38, generating mRNA transcripts that define LKs. Adhesion to deposits of laminin 5 via alpha 6 beta 4 suppresses P-p38 and activation mRNAs including ATF3. Defects in laminin 5 and alpha 6 beta 4 sustain P-p38 with probable pathological effects on transcription and migration.

关键词： ATF3   c-Myc   cell cycle progression   crosstalk   VASCULAR ENDOTHELIAL-CELLS   REGENERATING LIVER   PROTEIN STABILITY   INDUCED APOPTOSIS   DOWN-REGULATION   CYCLIN D1   EXPRESSION   ACTIVATION   IDENTIFICATION   TRANSCRIPTION  

摘要： The c-myc proto-oncogene encodes a transcription factor that promotes cell cycle progression and cell proliferation, and its deficiency results in severely retarded proliferation rates. The ATF3 stress response gene encodes a transcription factor that plays a role in determining cell fate under stress conditions. Its biological significance in the control of cell proliferation and its crosstalk regulation, however, are not well understood. Here, we report that the serum response of the ATF3 gene expression depends on c-myc gene and that the c-Myc complex at ATF/CREB site of the gene promoter plays a role in mediating the serum response. Intriguingly, ectopic expression of ATF3 promotes proliferation of c-myc-deficient cells, mostly by alleviating the impeded G1-phase progression observed in these cells, whereas ATF3 knockdown significantly suppresses proliferation of wild-type cells. Our study demonstrates that ATF3 is downstream of the c-Myc signaling pathway and plays a role in mediating the cell proliferation function of c-Myc. Our results provide a novel insight into the functional link of the stress response gene ATF3 and the protooncogene c-myc.

关键词： ATF3   p53   stability   stress   ubiquitination   PROLYL ISOMERASE PIN1   PROTEASOME-MEDIATED DEGRADATION   NUCLEAR EXPORT   GENE-EXPRESSION   MDM2   APOPTOSIS   PROTEIN   DOMAIN   REPRESSION   ATF3  

摘要： Activating transcription factor 3 (ATF3) is rapidly induced by diverse environmental insults including genotoxic stress. We report herein that its interaction with p53, enhanced by genotoxic stress, stabilizes the tumor suppressor thereby augmenting functions of the latter. Overexpression of ATF3 ( but not a mutated ATF3 protein (Delta 102- 139) devoid of its p53-binding region) prevents p53 from MDM2-mediated degradation and leads to increased transcription from p53-regulated promoters. ATF3, but not the Delta 102- 139 protein, binds the p53 carboxy-terminus and diminishes its ubiquitination and nuclear export. Genotoxic-stressed ATF3-null mouse embryonic fibroblasts, or cells in which ATF3 was reduced by small interference RNA, show inefficient p53 induction and impaired apoptosis compared with wild-type cells. ATF3-null cells ( but not wild-type cells), which poorly accumulate p53, are transformed by oncogenic Ras. Thus, ATF3 is a novel stress-activated regulator of p53 protein stability/ function providing the cell with a means of responding to a wide range of environmental insult, thus maintaining DNA integrity and protecting against cell transformation.

关键词： AXONAL transport   BIOLOGICAL transport   SENSORY neurons   NERVOUS system  

摘要： Abstract: In the present study, we investigated if the previously observed JNK-mediated activation of c-Jun and induction of ATF3 could be ascribed to axonal transport of JNK signaling components, or if axonal transport of the transcription factors themselves contributes to the nuclear changes in injured sensory neurons. We observed retrograde axonal transport of a number of JNK upstream kinases in ligated rat sciatic nerve. In these preparations, axonal transport of JNK/p-JNK, the JNK scaffolding protein JIP, and the transcription factors ATF3 and ATF2/p-ATF2 was also found. No or little retrograde transport of c-Jun and p-c-Jun was found, whereas an anterograde transport of Hsp27, a protein previously reported in the context of p-c-Jun and ATF3, was observed. In separate experiments, we found that in vitro inhibition of axonal transport or axonal inhibition of JNK reduced the number of p-c-Jun- and ATF3-positive neuronal nuclei. The results suggest that retrograde axonal transport of JNK signaling components contributes to the injury induced c-Jun phosphorylation and ATF3 induction. [Copyright &y& Elsevier]

关键词： DORSAL-ROOT GANGLIA   PROTEINS FOLLOWING AXOTOMY   NERVE GROWTH-FACTOR   TRANSCRIPTION FACTOR   PERIPHERAL-NERVE   APLYSIA NEURONS   NEUROPEPTIDE EXPRESSION   SCAFFOLD PROTEINS   RESPONSE ELEMENT   MOTOR-NEURONS  

摘要： In the present study, we investigated if the previously observed JNK-mediated activation of c-Jun and induction of ATF3 could be ascribed to axonal transport of JNK signaling components, or if axonal transport of the transcription factors themselves contributes to the nuclear changes in injured sensory neurons. We observed retrograde axonal transport of a number of JNK upstream kinases in ligated rat sciatic nerve. In these preparations, axonal transport of JNK/p-JNK, the JNK scaffolding protein JIP, and the transcription factors ATF3 and ATF2/p-ATF2 was also found. No or little retrograde transport of c-Jun and p-c-Jun was found, whereas an anterograde transport of Hsp27, a protein previously reported in the context of p-c-Jun and ATF3, was observed. In separate experiments, we found that in vitro inhibition of axonal transport or axonal inhibition of JNK reduced the number of p-c-Jun- and ATF3-positive neuronal nuclei. The results suggest that retrograde axonal transport of JNK signaling components contributes to the injury induced c-Jun phosphorylation and ATF3 induction. (c) 2005 Elsevier Inc. All rights reserved.

关键词： nerve compression   nerve injury   transcription factor   ATF3   regeneration   tetanic muscle force   muscle   RAT SCIATIC-NERVE   WALKING TRACK ANALYSIS   SENSORY NEURONS   SCHWANN-CELLS   REGENERATION   INJURY   GENE   EXPRESSION   PROTEINS   SIGNALS  

摘要： Nuclear translocation of activating transcription factor 3 (ATF3), used as a marker for neuronal injury, was studied by immunocytochemistry in sensory neurons in dorsal root ganglia and locally along the sciatic nerve after severe chronic nerve compression in rats. In compressed nerves (application of a narrow silicone tube), ATF3 immunoreactivity was seen in the nucleus of sensory neurons and in Schwann cells below the compression at two and four weeks. Removal of the silicone tube (decompression) at two weeks did not affect the number of ATF3-positive cell nuclei in dorsal root ganglia. No ATF3 immunoreactivity was found in undamaged nerves on the other side. Functional variables (toe spreading and muscle force) were impaired at two weeks, with partial improvement at four weeks. Nerve compression induces nuclear translocation of ATF3, a transcription factor associated with survival and regeneration of sensory neurons. The response is related to duration of compression and partly correlated to function.