关键词： Activating transcription factor 3 (ATF3)   Adaptive-response network   Inflammatory response  

摘要： Activating transcription factor 3 (ATF3) gene encodes a member of the ATF family of transcription factors and is induced by various stress signals. All members of this family share the basic region-leucine zipper (bZip) DNA binding motif and bind to the consensus sequence TGACGTCA in vitro. Previous reviews and an Internet source have covered the following topics: the nomenclature of ATF proteins, the history of their discovery, the potential interplays between ATFs and other bZip proteins, ATF3-interacting proteins, ATF3 target genes, and the emerging roles of ATF3 in cancer and immunity (see footnote 1). In this review, we present evidence and clues that prompted us to put forth the idea that ATF3 functions as a "hub" of the cellular adaptive-response network. We will then focus on the roles of ATF3 in modulating inflammatory response. Inflammation is increasingly recognized to play an important role for the development of many diseases. Putting this in the context of the hub idea, we propose that modulation of inflammation by ATF3 is a unifying theme for the potential involvement of ATF3 in various diseases.

关键词： LRF-1/ATF3   Hepatocytes   G protein-coupled receptors   Vasopressin   Ca2   Mitogen-activated protein kinases  

摘要： Background/Aims: Liver regeneration factor 1 (LRF1/ATF3) is an early response gene which is rapidly induced upon partial hepatectomy in rats, and by growth factors and G protein-coupled receptor (GPCR) agonists in cultured rat hepatocytes. The aim of the present study was to examine the mechanisms involved in induction of LRF-1/ATF3 by the GPCR agonist vasopressin. Methods: Primary cultures of rat hepatocytes were treated with vasopressin, TPA, and the Ca2+-elevating agents thapsigargin and A23187. LRF-1/ATF3 mRNA and protein were measured by Northern blot analysis or RT-PCR and immunoblotting. Signalling pathways were examined by immunoblots and kinase assays. Results: While elevation of intracellular calcium induced LRF-1/ATF3 expression, treatment with TPA did not. Inhibition of phospholipase C, protein kinase C, or pretreatment with calcium chelators did not affect vasopressin-induced expression of LRF-1/ATF3. Inhibition of each of the MAP kinases ERK1/2, JNK or p38 did not affect vasopressin-induced LRF-1/ATF3 expression. Combined inhibition of JNK and p38, and of ERK1/2 and either JNK or p38 suppressed vasopressin-induced expression of LRF-1/ATF3. Conclusion: Vasopressin induces LRF-1/ATF3 expression by mechanisms that differ from those activated by Ca2+-elevating agents. The results suggest that partly redundant, complex MAP kinase networks are involved in induction of LRF-1/ATF3 by vasopressin in hepatocytes. Copyright (C) 2010 S. Karger AG, Basel

关键词： 尿道下裂   转录激活因子3   结缔组织生长因子   17-β乙炔雌二醇  

摘要： 目的:雌激素与尿道下裂的发生关系密切,本研究旨在比较尿道下裂患儿包皮和同龄正常儿童包皮中转录激活因子3(ATF3)和结缔组织生长因子(CTGF)的表达,明确二者与尿道下裂的关系,探寻雌激素引起尿道下裂的分子机制。方法:从包皮中分离成纤维细胞并原代培养,用不同浓度(1.0μmol/L、0.1μmol/L、10.0nmol/L、1.0nmol/L、0.1nmol/L)的17-β乙炔雌二醇(17-EE)处理2h,或选择0.1μmol/L的17-EE处理不同时间(0.5、1、2、4、8、16、24h),观察17-EE对ATF3和CTGF表达的影响。MTT法检测17-EE对细胞增殖的影响,RT-PCR法观察成纤维细胞ATF3和CTGF表达情况。结果:尿道下裂患者包皮中ATF3和CTGF的表达显著高于正常人包皮组织(P<0.05);高浓度的17-EE干预对包皮成纤维细胞有抑制作用;在17-EE干预早期(1～2h)ATF3的表达呈现一过性增加;CTGF的表达在24h内17-EE干预未见明显变化。结论:ATF3和CTGF是与尿道下裂密切相关基因,雌激素可能通过上调ATF3和CTGF的表达参与调节生殖结节的异常发育,导致尿道下裂。

关键词： 尿道下裂   转录因子   免疫组织化学  

摘要： 目的探讨转录激活因子3(ATF3)在尿道下裂组织中的表达及其与尿道下裂程度的关系。方法收集28例尿道下裂组织,其中轻中度22例,重度6例,相应的正常环切包皮15例,采用免疫组化法检测ATF3的表达,分析蛋白阳性表达率。收集24例尿道下裂组织,其中轻中度8例,重度16例,对照为相应的正常环切包皮19例,采用RT-PCR法检测ATF3 mRNA的表达。结果ATF3蛋白在尿道下裂组织中表达阳性率为85.7%(24/28),在正常包皮组织中的表达阳性率为13.3%(2/15),ATF3蛋白在尿道下裂组织中的表达阳性率明显高于在正常包皮组织中的表达。重度尿道下裂ATF3蛋白阳性率100%(6/6),高于轻中度尿道下裂中的表达,在轻中度尿道下列中的表达为81.8%(18/22)。RT-PCR显示ATF3 mRNA表达在正常包皮组织、轻中度、重度尿道下裂组织中的相对累计光密度值比分别为(0.58±0.21)、(1.81±0.22)和(3.55±0.27),3组中的两两比较差异均有统计学意义。结论ATF3在尿道下裂组织中的表达明显上调,且与尿道下裂的程度显著相关,提示ATF3可能是尿道下裂发生中的一个候选基因。

关键词： Diabetic liver injury   ATF3   STAT1   Streptozotocin (STZ)   Apoptosis  

摘要： It is well-established that the administration of streptozotocin accelerates diabetic liver injury as well as type-1 diabetes, however the underlying mechanisms are poorly understood. Here we investigated the molecular mechanisms of diabetic liver injury in a model of streptozotocin (STZ)-induced type-1 diabetes. STZ administration induced type-1 diabetes and chronic liver injury was associated with increased STAT1, which is implicated in diabetic liver injury by virtue of its ability to promote hepatocyte apoptosis, in the liver and pancreas, which were all strongly inhibited in STAT1(-/-) mice. Similarly, STZ-induced ATF3, a stress-inducible gene, was completely abolished in the liver of IFN-gamma(-/-) mice, but not in STAT1(-/-) mice. Inhibition of STAT1 by siRNA or dominant-negative DNA did not affect ATF3 protein expression but blocked IFN-gamma-induced ATF3 translocation from the cytosol into the nucleus. In contrast, inhibition of ATF3 by using siRNA diminished STAT1 protein expression and IFN-gamma/STZ-induced hepatocyte apoptosis. Furthermore, GST pull-down and co-IP assay showed that STAT1 bound to C-terminal domain of ATF3. Such direct interaction increased the stability of STAT1 by inhibiting its ubiquitination as well as proteasome activity. Our results suggest that STAT1 is a common signaling pathway contributing to STZ-induced diabetes and diabetic liver injury. ATF3 functions as a potent regulator of STAT1 stability, accelerating STZ-induced diabetes and diabetic liver injury. (C) 2009 Elsevier Inc. All rights reserved.

关键词： experimental glaucoma   IOP elevation   neurotrophin   Trk receptor   p75(NTR)   Atf3  

摘要： Reduced retrograde transport of neurotrophins (NT) and their receptors has been hypothesized to contribute directly to retinal ganglion cell (RGC) loss in glaucoma. However, strategies of supplementing NT and NT receptors have failed to avert ultimate RGC death in experimental glaucoma. This study examines the response of major components of the NT system and their interacting proteins in a rat glaucoma model. Unilateral chronic intraocular pressure (IOP) elevation was produced by episcleral vein injection of hypertonic saline (N = 99). Retinas were collected and grouped by extent of optic nerve injury. Quantitative reverse transcription PCR, western blot analysis and immunohistochemistry were used to determine mRNA and protein levels and protein localization. Out of three RGC-specific Brn3 proteins (Brn3a, b, and c), only Brn3a was significantly downregulated at the message level to 35 +/- 4% of fellow values with the severest nerve injury. With IOP elevation, no significant alterations were found in retinal mRNA levels for BDNF, NGF, NT-4/5 or NT-3. The abundance of mature retinal BDNF protein was not significantly affected by elevated IOP, while proBDNF protein decreased linearly with increasing injury grade (r(2) = 0.50). In retinas with the severest nerve injury, TrkB and TrkC receptor mRNA levels significantly declined to 67 +/- 9% and 44 +/- 5% of fellow values, respectively. However, the levels of TRKB protein and its phosphorylated form were unchanged. Message level for p75(NTR) was linearly upregulated up to 219 +/- 26% with increasing injury (r(2) = 0.46), but no alteration was detected at protein level. The mRNA expression of p75(NTR) apoptosis adaptor proteins NADE, NRIF, and Lingo1 were significantly downregulated in retinas with the greatest nerve injury. A positive correlation was found between injury extent and message levels for Jun (r(2) = 0.23) as well as Junb (r(2) = 0.27), and RGC labeling of activated JUN protein increased. Atf3 mRNA levels de

关键词： ATF3   Transcriptional regulation   Immunity   TLRs   Oncogenesis   Gene expression  

摘要： Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP response element-binding (ATF/CREB) family of transcription factors. It is an adaptive-response gene that participates in cellular processes to adapt to extra- and/or intracellular changes, where it transduces signals from various receptors to activate or repress gene expression. Advances made in understanding the immunobiology of Toll-like receptors have recently generated new momentum for the study of ATF3 in immunity. Moreover, the role of ATF3 in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers.