关键词： elevated plus maze   anhedonia   porsolt   forced swim test   addiction   anxiety   drugs of abuse   stimulants   CREB   CREM   striatum   sucrose preference   neophobia   behavior   CRE-BP1   CREB2  

摘要： Previous research has shown that cAMP response element ( CRE) binding protein ( CREB) in the nucleus accumbens gates behavioral responses to emotional stimuli. For example, overexpression of CREB decreases anxiety, sucrose preference, and sensitivity to drugs of abuse and increases depression-like behavior, whereas blocking CREB via overexpression of inducible cAMP early repressor ( ICER) or other dominant-negative inhibitors of CRE-mediated transcription has the opposite effects. However, CREB and ICER are but two members of a larger family of leucine zipper-containing transcription factors composed of multiple products of the creb, crem ( cAMP response element modulator), and atf ( activating transcription factor) genes. We demonstrate here that ATF2, ATF3, and ATF4 are each robustly induced in the nucleus accumbens and dorsal striatum by restraint stress or by amphetamine administration. In contrast, little induction is seen for ATF1 or CREM. Using viral-mediated gene transfer, we show that ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressant-like responses, a behavioral phenotype similar to that caused by dominant-negative antagonists of CREB. In contrast, ATF3 or ATF4 overexpression in nucleus accumbens decreases emotional reactivity and increases depression-like behavior, consistent with the behavioral phenotype induced by CREB. Because amphetamine and stress induce ATF2, ATF3, and ATF4 in nucleus accumbens, and overexpression of these transcription factors in this brain region in turn alters behavioral responsiveness to amphetamine and stress, our findings support novel roles for these ATF family members in regulating emotional behavior.

关键词： cytomegalovirus   infectious disease   transcription factor   viral immunity  

摘要： Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3-deficient mice are more susceptible to endotoxic shock. Here, we demonstrate that ATF3 interacts with a cis-regulatory element of the IFN-gamma gene in natural killer(NK) cells, and that ATF3 null NK cells show increased transcription and secretion of IFN-gamma. NK cell-derived IFN-gamma has previously been demonstrated to be protective against murine cytomegalovirus (MCMV) infection, and we show here that ATF3 null mice exhibit decreased hepatic viral load and reduced liver histopathology upon challenge with MCMV. Reconstitution of NK-deficient mice with ATF3 null NK cells more effectively controlled MCMV infection than mice reconstituted with WT cells, indicating that ATF3 acts within NK cells to regulate antiviral responses.

关键词： ATF3   JNK   c-Jun   apoptosis   cerebellar granule neurons  

摘要： Cerebellar granule neurons (CGNs) depend on potassium depolarization for survival and undergo apoptosis when deprived of depolarizing concentration of potassium. Activating transcription factor 3 (ATF3), a stress-inducible protein, belongs to the ATF/CREB family of transcription factors family and is involved in cell growth and apoptosis. However, the role of ATF3 in neuronal apoptosis remains unknown. Here, we showed that ATF3 was up-regulated under potassium deprivation in CGNs, and this induction was preceded by a rapid and sustained activation of c-Jun NH2-terminal kinase/c-Jun signaling pathway, which plays a fundamental role in neuronal apoptosis. Furthermore, ATF3 upregulation was abolished by inhibition of JNK or knockdown of c-Jun. Finally, knockdown of ATF3 by RNA interference protected CGNs from potassium deprivation-induced apoptosis. Taken together, our results indicate that ATF3 is a downstream target of JNK/c-Jun pathway and contributes to apoptosis induced by potassium deprivation in rat CGNs. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.

摘要： Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.

关键词： pc-Jun   ATF3   MFB axotomy   substantia nigra   dopaminergic neuron   neurodegeneration   activated microglia  

摘要： Accumulating evidence has shown that both phosphorylated c-Jun (pc-Jun) and activating transcription factor 3 (ATF3) were upregulated in a variety of tissue injuries and proposed to play an important role in cell death/survival. To elucidate the significance and functional role of these immediate-early genes during neuronal damage in the central nervous system, we examined temporal and spatial profiles of pc-Jun and ATF3 in dopaminergic neurons of the substantia nigra (SN) following transection of the medial forebrain bundle (MFB) in adult rats. Morphological characteristics of pc-Jun-positive dopaminergic neurons as well as microglial reaction in response to the axotomy-induced neurodegeneration were also investigated. Following MFB transection, both c-Jun phosphorylation and ATF3 were found in the nuclei of tyrosine hydroxylase-immunoreactive (TH-ir) neurons of the ipsilateral SN, but not in those of the contralateral SN. In the ipsilateral SN, the number of pc-Jun- and ATF3-positive nuclei was increased by 5-7 days post-lesion, and then progressively decreased probably due to the loss of neurons. Retrograde tracing with FluoroGold (FG) in hemi-axotomized rat brain demonstrated that none of the intact, unaxotomized (FG-ir) neurons was pc-Jun-positive, indicating phosphorylation of c-Jun occurs only in axotomized neurons. Concomitant co-localization of pc-Jun and ATF3 in the same TH-ir neuron was also demonstrated by triple immunofluorescence labeling. Many TH-ir neurons that underwent various steps of consecutive neurodegenerative changes retained pc-Jun in the condensed or fragmented nuclei. Moreover, numerous activated microglia, identified by both phagocytic (ED1) and MHC II (OX6) markers, closely apposed to these neurons throughout the entire neurodegenerative process, suggesting that they are actively phagocytosing dying neurons. Taken together, these results support the idea that pc-Jun and its putative dimeric partner ATF3 may be closely participating in ax

关键词： berberine   NAG-1   ATF3   apoptosis   p53  

摘要： Berberine is known to possess a wide variety of pharmacological activities, including pro-apoptotic activity. However, its molecular targets are not elucidated at present. NAG-1 and ATF3 are induced by several dietary compounds associated with pro-apoptotic activity. Berberine induces cell growth arrest, apoptosis, NAGA, and ATF3 in human colorectal cancer cells. ATF3 induction by berberine is mediated in a p53-dependent manner, whereas NAG-I induction by berberine is mediated by multiple signaling pathways. Our results suggest that berberine facilitates apoptosis and that NAG-1 and ATF3 expression plays an important role in berberine-induced apoptosis. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

关键词： neuropathic pain   dorsal root ganglion   equine laminitis   neuronal injury marker   ATF3  

摘要： Laminitis is a common debilitating disease in horses that involves painful disruption of the lamellar dermo-epidermal junction within the hoof. This condition is often refractory to conventional anti-inflammatory analgesia and results in unremitting pain, which in severe cases requires euthanasia. The mechanisms underlying pain in laminitis were investigated using quantification of behavioural pain indicators in conjunction with histological studies of peripheral nerves innervating the hoof. Laminitic horses displayed consistently altered or abnormal behaviours such as increased forelimb lifting and an increased proportion of time spent at the back of the box compared to normal horses. Electron micrographic analysis of the digital nerve of laminitic horses showed peripheral nerve morphology to be abnormal, as well as having reduced numbers of unmyelinated (43.2%) and myelinated fibers (34.6%) compared to normal horses. Sensory nerve cell bodies innervating the hoof, in cervical, C8 dorsal root ganglia (DRG), showed an upregulated expression of the neuronal injury marker, activating transcription factor-3 (ATF3) ill both large NF-200-immunopositive neurons and small neurons that were either peripherin- or IB4-positive. A significantly increased expression of neuropeptide Y (NPY) was also observed in myelinated afferent neurons. These changes are similar to those reported in other neuropathic pain states and were not observed in the C4 DRG of laminitic horses, which is not associated with innervation of the forelimb. This study provides novel evidence for a neuropathic component to the chronic pain state associated with equine laminitis, indicating that anti-neuropathic analgesic treatment may well have a role in the management of this condition. (c) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.