关键词： exosomes   transcription factor   ATF3   AKI   WT-1   FSGS   GELATINASE-ASSOCIATED LIPOCALIN   ACUTE KIDNEY INJURY   GLOMERULAR-FILTRATION-RATE   MESSENGER-RNA EXPRESSION   GENE-EXPRESSION   CYSTATIN-C   ISCHEMIA-REPERFUSION   DIAGNOSTIC MARKER   SERUM CREATININE   TARGET GENES  

摘要： Urinary exosomes are excreted from all nephron segments and constitute a rich source of intracellular kidney injury biomarkers. To study whether they contain transcription factors, we collected urine from two acute kidney injury models (cisplatin or ischemia-reperfusion), two podocyte injury models (puromycin-treated rats or podocin-Vpr transgenic mice) and from patients with focal segmental glomerulosclerosis, acute kidney injury and matched controls. Exosomes were isolated by differential centrifugation and found to contain activating transcription factor 3 (ATF3) and Wilms Tumor 1 (WT-1) proteins detected by Western blot. These factors were found in the concentrated exosomal fraction, but not in whole urine. ATF3 was continuously present in urine exosomes of the rat models following acute injury at times earlier than the increase in serum creatinine. ATF3 was found in exosomes isolated from patients with acute kidney injury but not from patients with chronic kidney disease or controls. Urinary WT-1 was present in animal models before significant glomerular sclerosis and in 9/10 patients with focal segmental glomerulosclerosis but not in 8 controls. Our findings suggest that transcription factor ATF3 may provide a novel renal tubular cell biomarker for acute kidney injury while WT-1 may detect early podocyte injury. Measurement of urinary exosomal transcription factors may offer insight into cellular regulatory pathways.

关键词： UV   Hif-2alpha   apoptosis   ATF3   TRAIL   ACTIVATING TRANSCRIPTION FACTOR-3   GENE-EXPRESSION PATTERNS   HYPOXIA-INDUCIBLE FACTOR-2-ALPHA   VASCULAR ENDOTHELIAL-CELLS   ATF3 GENE   CANCER   OLIGONUCLEOTIDE   INDUCTION   KINASE   GROWTH  

摘要： In this study, we describe a novel activating transcription factor 3 (ATF3)-dependent death pathway triggered by ultraviolet (UV) irradiation. We demonstrate that ATF3 contributes to UV-induced apoptosis through the regulation of hypoxia inducible factor (Hif)-2alpha expression, which in turn induces the expression of proapoptotic genes, such as Caspase7 or TRAIL (tumor necrosis factor (ligand) superfamily, member 10). Gain of function of Hif-2alpha as well as ATF3 is sufficient to trigger cell death, whereas loss of function of both proteins drastically inhibits UV-induced apoptosis. Repression of Hif-2alpha strongly impairs ATF3-mediated death, providing evidences that Hif-2alpha is the major death effector of ATF3. In addition, Hif-1alpha, already known as a proapoptotic gene, upon UV irradiation, is not able to compensate for the lack of Hif-2alpha expression, thereby confirming the major contribution of Hif-2alpha in UV-mediated cell death. We further demonstrate that this cascade of gene activation depends on p38 and c-Jun N-terminal kinase (JNK) activity. Impairment of such a pathway is likely to contribute to oncogenesis by promoting survival of cells that could accumulate severe chromosomal alterations.

关键词： neuropathic pain   trigeminal   microglia   minocycline   IL-6   ATF3   CHRONIC CONSTRICTION INJURY   PERIPHERAL-NERVE INJURY   ROOT GANGLION NEURONS   SENSORY NEURONS   SPINAL-CORD   MICROGLIAL ACTIVATION   MECHANICAL ALLODYNIA   TRIGEMINAL GANGLION   INFRAORBITAL NERVE   NITRIC-OXIDE  

摘要： Responses resulting from injury to the trigeminal nerve exhibit differences compared with those caused by lesion of other peripheral nerves. With the aim of elucidating the physiopathological mechanisms underlying cephalic versus extracephalic neuropathic pain, we determined the time course expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1 beta, neuronal injury (ATF3), macrophage/microglial (OX-42), and satellite cells/astrocyte (GFAP) markers in central and ganglion tissues in rats that underwent unilateral chronic constriction injury (CCI) to either infraorbital nerve (IoN) (cephalic area) or sciatic nerve (SN) (extracephalic area). Whereas CCI induced microglial activation in both models, we observed a concomitant upregulation of IL-6 and ATF3 in the ipsilateral dorsal horn of the lumbar cord in SN-CCI rats but not in the ipsilateral spinal nucleus of the trigeminal nerve (Sp5c) in IoN-CCI rats. Preemptive treatment with minocycline (daily administration of 20 mg/kg, i.p., for 2 weeks) partially prevented pain behavior and microglial activation in SN-CCI rats but was ineffective in IoN-CCI rats. We show that IL-6 can upregulate OX-42 and ATF3 expression in cultured microglia and neurons from spinal cord, respectively, as well as in the dorsal horn after acute intrathecal administration of the cytokine. We propose that IL-6 could be one of the promoters of the signaling cascade leading to abnormal pain behavior in SN-CCI but not IoN-CCI rats. Our data further support the idea that different pathophysiological mechanisms contribute to the development of cephalic versus extracephalic neuropathic pain.

关键词： serotonin   serotonin-transporter   ATF3   intraepidermal nerve fibres   inflammatory pain   PRIMARY AFFERENTS   5-HT TRANSPORTER   DEFICIENT MICE   KNOCKOUT MICE   RAT   PAIN   EXPRESSION   BRAIN   GENE   MEDIATORS  

摘要： Mice lacking the serotonin-transporter (5-HTT-/- mice) develop reduced thermal hyperalgesia after nerve injury, concomitant with reduced serotonin (5-HT) levels in nervous tissue. Here we investigated pain behaviour in 5-HTT-/- mice compared to their wild type littermates after hind paw inflammation induced by complete Freund's adjuvant (CFA). We used standard tests for pain behaviour, high performance liquid chromatography for measurement of 5-HT, and immunohistochemistry of hind paw skin tissue and L5 dorsal root ganglia (DRG) to measure local inflammation and nerve injury. After intraplantar CFA injection, hyperalgesia to heat was attenuated in 5-HTT-/- mice compared to wild type mice. Their 5-HT levels in nervous and adrenal tissue were reduced. An intraplantar injection of 5-HT four days after CFA transiently brought withdrawal latencies of 5-HTT-/- mice down to the level of wild type mice, thus rescuing the phenotype and supporting the role of 5-HT in the development of CFA-induced thermal hyperalgesia. The density of intraepidermal nerve fibres in plantar skin after CFA injection was reduced to a higher degree in 5-HTT-/- mice than in wild type mice, suggesting greater peripheral nerve injury in the knock-out mice during hind paw inflammation. Accordingly, a higher number of injured DRG neurons was identified by activating transcription factor 3 (ATF3) staining in 5-HTT-/- mice after CFA. We conclude that the phenotype of 5-HTT-/- mice leads to reduced inflammatory pain due to reduced tissue 5-HT levels and to greater peripheral nerve injury after inflammation. Human variants of the 5-HTT genotypes might be part of the factors determining the extent of nerve injury and hyperalgesia in inflammation. (C) 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.

关键词： AMPK   AM251   cannabinoid antagonist   JNK   ATF3   CANNABINOID SYSTEM   ENERGY-BALANCE   CANCER CELLS   FOOD-INTAKE   KEY SENSOR   APOPTOSIS   ATF3  

摘要： AM251, a cannabinoid antagonist, has various biological activities. In this study, we found that AM251 suppressed the viability of hepatoma HepG2 cells and also increased phosphorylation of JNK (c-jun N-terminal kinase) and ATF3 (activating transcription factor 3). In addition, AM251 phosphorylated AMPK (AMP-activated protein kinase) in a time and dose-dependent manner. Inhibition of AMPK blocked AM251-induced JNK/ATF3 phosphorylation. Expression of AMPK or treatment with AICAR (5-aminoimidazole-4-carboxy-amide-1-D-ribofuranoside), an AMPK activator, activated the JNK/ATF3 pathways. Together, these results suggest that AM251 may have anti-tumor effects in hepatoma through activation of the AMPK-JNK-ATF3 signal pathway. (c) 2008 Published by Elsevier Inc.

摘要： Introduction ATF3, gène œstrogéno-dépendant exprimé durant le développement génital, est considéré comme un gène candidat de l’hypospadias du fait de son expression anormalement élevée dans le prepuce d’hypospades, et du fait de son implication dans l’arrêt du cycle cellulaire qui pourrait interférer avec la croissance urétrale. Le but de cette étude est de préciser l’implication d’ATF3 dans l’hypospadias en réalisant son séquençage chez des patients hypospades et en étudiant son expression dans le tubercule génital de fœtus humains. Matériel et méthode Le séquençage des exons codants et des sites d’épissage d’ATF3 a été réalisé chez 41 garçons porteurs d’hypospadias de sévérité variable et chez 30 contrôles. L’expression d’ATF3 dans le tubercule génital de fœtus humains avec et sans hypospadias a été étudiée par immunohistochimie. Résultats - La mutation missense (Leu23Met) a été identifiée chez un garcon porteur d’un hypospadias antérieur. Cette acide aminé, habituellement hautement conservé à travers les espèces, pourrait avoir un rôle fonctionnel significatif. - Trois mutations (C53070T, C53632A, Ins53943A) ont été identifiées dans ou à proximité de l’exon 6. Cette région importante comprend une zone d’épissage alternatif à l’origine de la fomre ATF3Δ zip. Cette forme alternative est impliquée dans la régulation de la fonction d’ATF3. Ces mutations pourraient donc être altérer sa formation et ainsi la régulation de l’action d’ATF3. Les phénotypes associés à ces mutations étaient des hypospadias périnéal, pénoscrotal et antérieur. Aucune mutation n’a été identifiée chez les contrôles. - ATF3 n’est pas exprimé dans l’urètre du fœtus normal. Il est par contre exprimé de façon aberrante dans la plaque urétrale chez le fœtus hypospade, en particulier au niveau de l’orifice urétral ectopique. Conclusion Nous rapportons les premières mutations du gène ATF3 chez des patients porteurs d’hypospadias. Ces résultats, associés à une expression aberrante d’ATF3 dans l’urètre

关键词： MMP   ADC   gene   enos   ATF3  

摘要： Objective In this study we will investigate the effect and possible mechanism of agmatine on MMP *** We established a transfection of human ADC gene into the murine bEnd.3 cells(bEnd.3-ADC)by the retroviral packaging cell line *** bEnd.3-ADC cells were maintained in the hypoxia chamber for 6 hours,then returned to a normoxic incubator with glucose for 16 *** performed RT-PCR and western blot analysis against MMP-2,MMP-9,eNOS and ATF3,and measured the production of NO using Griess *** determine the possible mechanism of agmatine on MMP expression we used inhibitory *** The expression of MMP was decreased by agmatine administered exogenously and endogenously,while eNOS was *** showed L-NAME(NOS inhibitor)altered the suppression of MMP-9 by exogenously administered *** seems that MMP-9 suppression by exogenously administrated agmatine is mediated,at least in part,via *** also found that ATF3 was increased significantly in ADC overexpression cells,but it was attenuated by NOS ***,we found the suppression of MMP by agmatine was attenuated in cells transfected with ATF3 *** Our study suggested that endogenously administered agmatine suppress the MMP-2 and MMP-9 expression via eNOS-ATF3-MMPs pathway.

关键词： RECEPTOR TYROSINE KINASE   ENDOTHELIAL GROWTH-FACTOR   TUMOR ANGIOGENESIS   PROTEIN   ATF3   INTEGRIN   ADHESION   FAMILY   VIVO   PROGRESSION  

摘要： ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro. Although tyrosine kinase activation of EphA1 was dispensable, binding of EphA1 to fibronectin through its type I repeat played an essential role in the angiogenesis. Recombinant proteins containing fibronectin 10th to 12th type I repeat (I10-12) but not I 12 could inhibit the angiogenesis in vitro by competitively targeting EphA1 with the full-length fibronectin. However, I 12 acquired a higher affinity toward EphA2 with K-d 18 nM and inhibited vascular endothelial growth factor-dependent angiogenic invasion in a Matrigel plug assay.