关键词： Senescence   Skin cancer  

摘要： Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population(1). By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent(1). Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-ras(V12) (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enlarged' AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.

关键词： AdipoR2   ATF3   ER stress   insulin resistance   obesity  

摘要： Adiponectin acts as an insulin-sensitizing adipokine that protects against obesity-linked metabolic disease, which is generally associated with endoplasmic reticulum (ER) stress. The physiological effects of adiponectin on energy metabolism in the liver are mediated by its receptors. We found that the hepatic expression of adiponectin receptor 2 (AdipoR2) was lower, but the expression of markers of the ER stress pathway, 78 kDa glucose-regulated protein (GRP78) and activating transcription factor 3 (ATF3), was higher in the liver of ob/ob mice compared with control mice. To investigate the regulation of AdipoR2 by ER stress, we added thapsigargin, an ER stress inducer, to a human hepatocyte cell line, HepG2. Addition of the ER stress inducer increased the levels of GRP78 and ATF3, and decreased that of AdipoR2, whereas addition of a chemical chaperone, 4-phenyl butyric acid (PBA), could reverse them. Up- or down-regulation of ATF3 modulated the AdipoR2 protein levels and AdipoR2 promoter activities. Reporter gene assays using a series of 5'-deleted AdipoR2 promoter constructs revealed the location of the repressor element responding to ER stress and ATF3. In addition, using electrophoretic mobility shift and chromatin immunoprecipitation assays, we identified a region between nucleotides -94 and -86 of the AdipoR2 promoter that functions as a putative ATF3-binding site in vitro and in vivo. Thus, our findings suggest that the ER stress-induced decrease in both protein and RNA of AdipoR2 results from a concomitant increase in expression of ATF3, which may play a role in the development of obesity-induced insulin resistance and related ER stress in hepatocytes.

摘要： Purpose Hypospadias is a common congenital malformation of the male external genitalia with a multifactorial etiology. Little is known about the genes involved in Hypospadias. A few genetic associat ions have been reported, but mainly in studies of small sample size. Most of these associations have not been replicated. The aim of this study was to investigate whether previously reported associations for four single nucleotide polymorphisms (SNPs) in genes involved in hormonal pathways could be replicated in a large Dutch Hypospadias sample. The SNPs investigated are rs523349 in steroid-5-alpha-reductase (SRD5A2), rs6932902 in estrogen receptor 1 (ESR1), rs2987983 in ESR2 and rs11119982 in activating transcription factor 3 (ATF3). Material and Methods We genotyped 620 Caucasian Hypospadias cases and 596 controls for the four SNPs using TaqMan-based genotyping. Results We did not replicate the associations of the SNPs in SRD5A2 and ESR1 with Hypospadias. The SNPs in ESR2 and ATF3 were borderline associated with Hypospadias (odds ratios 0.9 (95% confidence interval (CI) 0.7-1.0) and 1.2 (95% CI 1.0-1.4), respectively), but in the opposite direction compared to earlier publications. Stratification according to the localization of the urethral opening produced comparable results in the subgroups. Conclusions The lack of consistency between our and previously performed studies might represent spurious results or chance findings found in our or the earlier studies, differences in criteria used to select the study populations, or a real difference between the populations. These results once again confirm the importance of replication in genetic association approaches.

关键词： Activating Transcription Factor 3/physiology   Apoptosis/drug effects   Capsaicin/pharmacology   Capsaicin/pharmacology   CCAAT-Enhancer-Binding Protein-beta/physiology   Colorectal Neoplasms/drug therapy   Colorectal Neoplasms/pathology   Glycogen Synthase Kinase 3/physiology   Glycogen Synthase Kinase 3/physiology   Growth Differentiation Factor 15/genetics   Growth Differentiation Factor 15/physiology   HCT116 Cells   HT29 Cells   Humans   Phosphorylation   Promoter Regions, Genetic   Protein Kinase C/physiology   Receptors, Retinoic Acid/physiology   Signal Transduction  

摘要： Capsaicin, a natural product of the Capsicum species of red peppers, is known to induce apoptosis and suppress growth. Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and antitumorigenic property in colorectal and lung cancer. Our data demonstrate that capsaicin leads to induction of apoptosis and up-regulates NAG-1 gene expression at the transcriptional level. Overexpression of CCAAT/enhancer binding protein beta (C/EBP beta) caused a significant increase of basal and capsaicin-induced NAG-1 promoter activity. We subsequently identified C/EBP beta binding sites in the NAG-1 promoter responsible for capsaicin-induced NAG-1 transactivation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed binding of C/EBP beta to the NAG-1 promoter. Capsaicin treatment resulted in an increase of phosphorylated serine/threonine residues on C/EBP beta, and the immunoprecipitation study showed that capsaicin enhanced binding of C/EBP beta with glycogen synthase kinase 3 beta (GSK3 beta) and activating transcription factor 3 (ATF3). The phosphorylation and interaction of C/EBP beta with GSK3 beta and ATF3 are decreased by the inhibition of the GSK3 beta and Protein Kinase C pathways. Knockdown of C/EBP beta, GSK3 beta or ATF3 ameliorates NAG-1 expression induced by capsaicin treatment. These data indicate that C/EBP beta phosphorylation through GSK3 beta may mediate capsaicin-induced expression of NAG-1 and apoptosis through cooperation with ATF3 in human colorectal cancer cells.

摘要： 280

关键词： sublytic C5b-9   apoptosis   glomerular mesangial cell （GMC）   activating transcription factor 3 （ATF3）  

摘要： Sublytic complement C5b-9 complexes can cause cell apoptosis, but the mechanism of glomerular mesangial cell （GMC） apoptosis mediated by these complexes has not been well defined. The activating transcription factor 3 （ATF3） gene is an immediate early gene for the cell to cope with a variety of stress signals and can promote apoptosis of some cells. In this study, ATF3 expression and cell apoptosis in GMCs induced by sublytic C5b-9 were measured, and then the effects of ATF3 gene over-expression or knockdown on GMC apoptosis induced by sublytic C5b-9 were examined at a fixed time. The results showed that both ATF3 expression and GMC apoptosis were markedly increased and ATF3 over-expression obviously increased sublytic C5b-9-induced GMC apoptosis, whereas ATF3 gene silencing had a significant opposite effect. Collectively, these findings indicate that upregulation of ATF3 gene expression is involved in regulating GMC apoptosis induced by sublytic C5b-9 complexes.

关键词： Optic nerve regeneration   Zebrafish   ATF3   Differential gene expression   cAMP   Oligodendrocytes   Astrocytes   Retinal ganglion cells  

摘要： Fish, unlike mammals, can regenerate axons in the optic nerve following optic nerve injury. We hypothesized that using microarray analysis to compare gene expression in fish which had experienced optic nerve lesion to fish which had undergone a similar operation but without optic nerve injury would reveal genes specifically involved in responding to optic nerve injury (including repair), reducing detection of genes involved in the general stress and inflammatory responses. We discovered 120 genes were significantly (minimally two-fold with a P-value <= 0.05) differentially expressed (up or down) at one or more time point. Among these was ATF3, a member of the cAMP-response element binding protein family. Work by others has indicated that elevated cAMP could be important in axon regeneration. We investigated ATF3 expression further by qRT-PCR, in situ hybridization and immunohistochemistry and found ATF3 expression is significantly upregulated in the ganglion cell layer of the retina, the nerve fiber layer and the optic nerve of the injured eye. The upregulation in retina is detectable by qRT-PCR by 24 h after injury, at which time ATF-3 mRNA levels are 8-fold higher than in retinas from sham-operated fish. We conclude ATF3 may be an important mediator of optic nerve regeneration-promoting gene expression in fish, a role which merits further investigation. (C) 2009 Elsevier Inc. All rights reserved.

关键词： Dorsal root ganglion   Peripheral nerve injury   Nerve regeneration   Regeneration-associated gene   Fluorescent tracer  

摘要： Peripheral nerve injury leads to deficient recovery of sensation and a causative factor may be that only 50-60% of primary sensory neurons succeed in regenerating axons after primary nerve repair. In this study, an in vivo rat sciatic nerve injury and regeneration model was combined with laser microdissection and quantitative real-time polymerase chain reaction with the aim of examining the gene expression of regenerative molecules in cutaneous and muscular sensory neurons. Recent studies have identified peripherin and ATF-3 molecules as crucial for neurite outgrowth propagation;our novel findings demonstrate a subpopulation of non-regenerating sensory neurons characterized by a failure to upregulate transcription of these molecules and that a greater peripherin mRNA expression in injured cutaneous neurons may potentiate this subpopulation to regenerate more axons than muscle afferent neurons following injury. The gene expression of the structural neurofilament NF-H is found to be significantly downregulated following injury in both sensory subpopulations. (C) 2009 Elsevier B.V. All rights reserved.

关键词： 肿瘤细胞转化   ATF3   P53基因   正常细胞   遗传毒性   细胞凋亡   E2F1   癌基因  

摘要： 正常细胞向肿瘤细胞转化的微环境中,细胞会碰到很多的应激信号,包括遗传毒性的损害,癌基因的激活,端粒的侵蚀,缺氧,营养剥夺等。此时细胞中一些内在的机制就会被激活从而去抑制或减少它们的损害。明显的例子就是P53基因在应答中抑制或杀死这些细胞。还有的例子就是通过癌基因的应激引起c-myc和E2F1来触发细胞凋亡。在研究肿瘤的发生发展的机制中,[第一段]