摘要： 7-methylguanosine (m(7)G) modification is recently found to conservatively exist in RNA internal position besides mRNA caps and mediates the various RNA metabolisms. As the core confirmed transmethylase of m(7)G modification, METTL1 has been reported in certain human cancers. However, the role of internal m(7)G at miRNAs and its core writer METTL1 in bladder cancer (BCa) remains to be elucidated. Here, we demonstrated that METTL1 was indispensable for BCa proliferation and metastasis in vitro and in vivo. By combining miRNA sequencing, m(7)G methylated RNA immunoprecipitation (MeRIP) and RIP, we identified METTL1 promoted the processing of miR-760 in an m(7)G-dependent manner. Transcription sequencing suggested that METTL1 indirectly degrades tumor suppressor ATF3 mRNA mediated by miR-760. Together, we concluded a regulatory axis composed of METTL1/m(7)G/miR-760/ATF3 in regulating BCa progression and provided potential therapeutic targets for BCa.

关键词： Glucose starvation   ptau(S409)   PKAc alpha   ATF3  

摘要： In this work, we report that glucose starvation (GS) causes ptau(S409) increase, which may participate in GS-induced neurites retraction in neuro-2a (N2a) cells. Upon GS treatment, PKAc alpha was stimulated at mRNA and protein levels. Luciferase reporter gene assays indicated that GS regulated PKAc alpha expression through a core promoter (-345 to -95 bp upstream the transcription starting site) consisting of a cis-acting element of Activating Transcription Factor 3 (ATF3). Knockdown and over-expression experiments demonstrate that ATF3 transcriptionally regulated PKAc alpha expression. Moreover, GS stimulated ATF3 expression in a time-dependent manner. These findings reveal that glucose starvation induces ptau(S409) increase in N2a cells through an ATF3- PKAc alpha axis, which shed some light on the relationship between brain glucose metabolism and neurodegenerative diseases.

关键词： ATF3   Atherosclerosis   Angiogenesis   Inflammation   Endothelial cell plasticity  

摘要： Atherosclerosis, the pathophysiological basis of most malignant cardiovascular diseases, remains a global concern. Transcription factors play a key role in regulating cell function and disease progression in developmental signaling pathways involved in atherosclerosis. Activated transcription factor (ATF) 3 is an adaptive response gene in the ATF/cAMP response element binding (CREB) protein family that acts as a transcription suppressor or activator by forming homodimers or heterodimers with other ATF/CREB members. Appropriate ATF3 expression is vital for normal physiological cell function. Notably, ATF3 exhibits distinct roles in vascular endothelial cells, macrophages, and the liver, which will also be described in detail. This review provides a new perspective for atherosclerosis therapy by summarizing the mechanism of ATF3 in atherosclerosis, as well as the structure and pathophysiological properties of ATF3. Key messages center dot In endothelial cells, ATF3 overexpression aggravates oxidative stress and inflammation. center dot In macrophages and liver cells, ATF3 can act as a negative regulator of inflammation and promote cholesterol metabolism. center dot ATF3 can be used as a potential therapeutic factor in the treatment of atherosclerosis.

摘要： Purpose. Osteoporosis is a complication of type 2 diabetes, and it is characterized by reduced bone mass, augmented bone fragility, and increased risk of fracture, thus reducing patient quality of life, especially in the elderly. Ferroptosis has been implicated in the pathological process of type 2 diabetic osteoporosis (T2DOP), but the specific underlying mechanisms remain largely unknown. This study clarified the role of activating transcription factor 3 (ATF3) in T2DOP and explored its specific regulatory mechanism, providing a new treatment target for T2DOP. Methods. We cultured hFob1.19 cells in high glucose (HG, 35 mM) and knocked down ATF3 using short hairpin RNA (shRNA). We then measured cell viability, assessed morphology, quantified the expression of ATF3 and glutathione peroxidase 4 (GPX4), detected the levels of reactive oxygen species (ROS) and lipid peroxides, and determined the osteogenic function of osteoblasts. Cystine/glutamate antiporter (system Xc(-)) activity was evaluated by determining the expression of SLC7A11 and the levels of glutathione (GSH) and extracellular glutamate. We constructed a T2DOP rat model and observed the effect of ATF3 on ferroptosis and T2DOP by knocking down ATF3 using small interfering RNA (siRNA). Then, we evaluated the levels of iron metabolism, lipid peroxidation, and bone turnover in serum, detected the expression of ATF3, SLC7A11, and GPX4 in bone tissues, and assessed bone microstructure using microcomputed tomography. Results. ATF3 expression was increased in osteoblasts under HG condition and in T2DOP rats. Inhibiting the function of ATF3 increased GPX4 levels and reduced the accumulation of ROS and lipid peroxides. These changes inhibited the ferroptosis of osteoblasts and improved osteogenic function. In addition, HG induced ATF3 upregulation, resulting in decreased SLC7A11 expression and lower levels of intracellular GSH and extracellular glutamate. Conclusion. Osteoblast ferroptosis under HG conditions is ind

关键词： Data reanalysis   Data mining   JEV   Japanese   Encephalitis   miRNA   DEG   ATF3   MYH10   PAQR8   Innate   Antiviral   Microarray   RNA-Seq  

摘要： Purpose: Japanese encephalitis (JE), caused by the Japanese encephalitis virus (JEV), is the principal cause of viral encephalitis in South-East Asian and Western Pacific countries;accounting for 68,000 cases, and up to 20,400 fatalities, annually across the world. Despite being a high-risk condition, there is no specific treatment for JE. Given rapid additions in genomics databases and the power of data reanalysis in addressing critical medical questions, the present study was designed to identify novel host factors that might have potential roles in JEV ***: We extracted microarray and RNA-Seq data sets from NCBI-GEO and compared mock and JEV-infected samples. Raw data from all the studies were re-analyzed to identify host factors associated with JEV ***: We identified several coding and non-coding host factors that had no prior known role in viral infections. Of these, the coding transcripts: Myosin Heavy Chain 10 (MYH10), Progestin and AdipoQ Receptor Family Member 8 (PAQR8), and the microRNAs: hsa-miR-193b-5p, hsa-miR-3714 and hsa-miR-513a-5p were found to be novel host factors deregulated during JEV infection. MYH10 encodes a conventional non-muscle myosin, and mutations in MYH10 have been shown to cause neurological defects. PAQR8 has been associated with epilepsy, which exhibits symptoms similar to JEV infection. JE is a neuro-degenerative disease, and the known involvement of MYH10 and PAQR8 in neurological disorders strongly indicates potential roles of these host factors in JEV infection. Additionally, we observed that MYH10 and PAQR8 had a significant negative correlation with Activating transcription factor 3 (ATF3), which is a previously validated modulator of JEV infection. ATF3 is a transcription factor that binds to the promotors of genes encoding other transcription factors or interferonstimulated genes and negatively regulates host antiviral responses during ***: Our findings demonstrate the significance of

关键词： ATF3   glucolipid metabolism   metabolic organ   metabolic diseases  

摘要： Lipids and glucose exert many essential physiological functions,such as providing raw materials or energy for cellular biosynthesis,regulating cell signal transduction,and maintaining a constant body *** of lipid and glucose metabolism can lead to glucolipid metabolic disorders linked to various metabolic diseases,such as obesity,diabetes,and cardiovascular ***,intervention in glucolipid metabolism is a key therapeutic strategy for the treatment of metabolic *** transcription factor 3(ATF3)is a transcription factor that acts as a hub of the cellular adaptive-response network and plays a pivotal role in the regulation of inflammation,apoptosis,DNA repair,and *** evidence has illustrated the vital roles of ATF3 in glucolipid ***3 inhibits intestinal lipid absorption,enhances hepatic triglyceride hydrolysis and fatty acid oxidation,promotes macrophage reverse cholesterol transport,and attenuates the progression of western diet-induced nonalcoholic fatty liver disease and *** addition to its role in lipid metabolism,ATF3 has also been identified as an important regulator of glucose ***,we summarize the recent advances in the understanding of ATF3,mainly focusing on its role in glucose and lipid metabolism and potential therapeutic implications.

关键词： USP22   AP2   ATF3   NSCLC   Transcriptional regulation   Cell proliferation   Invasion   Malignancy  

摘要： Background: Ubiquitin-specific protease 22 (USP22), a putative cancer stem cell marker, is frequently upregulated in cancers, and USP22 overexpression is associated with aggressive growth, metastasis, and therapy resistance in various human cancers including lung cancer. However, USP22 gene amplification seldom occurs, and the mechanism underlying USP22 upregulation in human cancers remains largely unknown. Methods: A luciferase reporter driven by a promoter region of USP22 gene was selectively constructed to screen against a customized siRNA library targeting 89 selected transcription factors to identify potential transcription factors (TFs) that regulate USP22 expression in human non-small cell lung cancers (NSCLC). Association of identified TFs with USP22 and potential role of the TFs were validated and explored in NSCLC by biological assays and immunohistochemistry analysis. Results: Luciferase reporter assays revealed that SP1 and activating transcription factor 3 (ATF3) inhibit USP22 transcription, while transcription factor AP-2 Alpha/Beta (TFAP2A/2B) and c-Myc promote USP22 transcription. Binding site-directed mutagenesis and chromosome immunoprecipitation (ChIP) assays validated AP2a and AP213 are novel TFs of USP22. Furthermore, overexpression of AP2A and AP2B significantly upregulates USP22 expression, and its target: Cyclin D1, concurrently enhances the proliferation, migration, and invasion of NSCLC A549 and H1299 cells in a partially USP22-dependent manner. Moreover, AP2 protein level correlated with USP22 protein in human NSCLC tissues. Conclusion: Our findings indicate AP2 alpha and AP2 beta are important transcription factors driving USP22 gene expression to promote the progression of NSCLC, and further support USP22 as a potential biomarker and therapeutic target for lung cancer.

关键词： trogocytosis   cancer immunotherapy   cytotoxic T lymphocytes   CD8+ T lymphocytes   tumor-derived factors   chimeric antigen receptor   ATF3   CH25H   hydroxycholesterol   sumoylation inhibitor  

摘要： Effector trogocytosis between malignant cells and tumor-specific cytotoxic T lymphocytes (CTLs) contrib-utes to immune evasion through antigen loss on target cells and fratricide of antigen-experienced CTLs by other CTLs. The mechanisms regulating these events in tumors remain poorly understood. Here, we demon-strate that tumor-derived factors (TDFs) stimulated effector trogocytosis and restricted CTLs' tumoricidal ac-tivity and viability in vitro. TDFs robustly altered the CTL's lipid profile, including depletion of 25-hydroxycholesterol (25HC). 25HC inhibited trogocytosis and prevented CTL's inactivation and fratricide. Mechanistically, TDFs induced ATF3 transcription factor that suppressed the expression of 25HC-regulating gene-cholesterol 25-hydroxylase (CH25H). Stimulation of trogocytosis in the intratumoral CTL by the ATF3-CH25H axis attenuated anti-tumor immunity, stimulated tumor growth, and impeded the efficacy of chimeric antigen receptor (CAR) T cell adoptive therapy. Through use of armored CAR constructs or pharmacologic agents restoring CH25H expression, we reversed these phenotypes and increased the efficacy of immuno-therapies.

关键词： Myocardial ischemia   reperfusion   ATF3   Ferroptosis   FANCD2  

摘要： Introduction: Ferroptosis, a newly identified type of programmed cell death type, has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury. However, little is known about ferroptosis regulation in I/R ***: We identified activating transcription factor 3 (ATF3) as a vital regulator of I/R induced ferroptosis and investigated the effects and potential mechanism of ATF3 in cardiac ***: In this study, the dynamic RNA-sequencing (RNA-seq) analysis were performed on mouse hearts exposed to different I/R schedules to identify that ATF3 represents an important modulatory molecule in myocardial I/R injury. Then knockout, rescue and overexpression methods were used in mice and neonatal mouse cells (NMCs) to illustrate the effect of ATF3 on myocardial I/R injury. Loss/gain of function techniques were used both in vivo and in vitro to explore the effects of ATF3 on ferroptosis in I/R injury. Furthermore, chromatin immunoprecipitation sequence (ChIP-seq) analysis was performed in the AC16 human cardiomyocyte cell line to investigate potential genes regulated by ***: ATF3 expression reached highest level at early stage of reperfusion, knockout of ATF3 significantly aggravated I/R injury, which could be rescued by ATF3 re-expression. Knockout and the re-expression of ATF3 changed the transcription levels of multiple ferroptosis genes. In addition, results showed that overexpression of ATF3 inhibits cardiomyocyte ferroptosis triggered by erastin and RSL3. Lastly, ChIP-seq and dual luciferase activity analysis revealed ATF3 could bind to the transcription start site of Fanconi anaemia complementation group D2 (FANCD2) and increased the FANCD2 promoter activity. Furthermore, we first demonstrated that overexpression of FANCD2 exerts significant anti-ferroptosis and cardioprotective effect on AC16 cell H/R ***: ATF3 inhibits cardiomyocyte ferroptotic death in I/R injury, which might be related