摘要： (no summary available)

摘要： (no summary available)

关键词： Activating transcription factor 3   Apoptosis   BK polyomavirus   Cisplatin  

摘要： Recent evidence links BK polyomavirus (BKPyV) infection to an increased risk of bladder cancer. This study investigates the role of BKPyV and its microRNA, miR-B1, in cisplatin-induced apoptosis. PCR analysis detected BKPyV DNA in 3 of 22 urothelial carcinoma (UC) samples from a non-transplant population. Bladder cancer cells infected with BKPyV showed increased proliferation and miR-B1–3p and −5p expression. Bioinformatics analysis identified a miR-B1–5p target site in the 3′-UTR of activating transcription factor 3 (ATF3), confirmed by a luciferase assay. The inhibitory effect was further validated by reduced ATF3 mRNA levels following overexpression of miR-B1 vectors or 5p mimics. Cisplatin treatment upregulated ATF3 expression, as shown by qPCR and immunoblotting. Overexpression of ATF3 mitigated the cisplatin-induced reduction in cell viability and elevated apoptotic markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). BKPyV infection or large T antigen (TAg) overexpression suppressed cisplatin-induced ATF3 expression, reducing its cytotoxicity and apoptotic marker expression. However, overexpression of ATF3 in BKPyV-infected bladder cancer cells attenuated BKPyV's inhibitory effects, restoring cisplatin-induced cytotoxicity and apoptotic marker expression, suggesting BKPyV infection promotes resistance to cisplatin cytotoxicity. Transfection with miR-B1 vectors or miR-B1–5p mimics decreased cisplatin-induced annexin V-positive cells, caspase-3 activity, and apoptotic marker expression, indicating that miR-B1 suppresses cisplatin-induced apoptosis. In conclusion, this study demonstrates that BKPyV promotes bladder cancer cell growth and impairs cisplatin-induced apoptosis, with miR-B1 targeting ATF3 as a key mechanism. Targeting BKPyV replication or regulating miR-B1 expression could offer potential therapeutic strategies for managing BKPyV-positive and cisplatin-resistant urothelial carcinoma.

关键词： FADS1   PUFA   Kidney cancer   ER stress   ATF3  

摘要： Objective Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain polyunsaturated fatty acids (PUFAs). Increasing studies suggest that FADS1 is a potential cancer target. Our previous research has demonstrated the significant role of FADS1 in cancer biology and patient survival, especially in kidney cancers. We aim to explore the underlying mechanism in this study. Method and results We found that pharmacological inhibition or knockdown of the expression of FADS1 significantly reduced the intracellular conversion of long-chain PUFAs, effectively inhibits renal cancer cell proliferation, and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo . Mechanistically, we showed that while FADS1 inhibition induces endoplasmic reticulum (ER) stress, FADS1 expression is augmented by ER-stress inducer, suggesting a necessary role of PUFA production in response to ER stress. FADS1-inhibition sensitized cellular response to ER stress inducers, leading to cell apoptosis. Also, FADS1 inhibition-induced ER stress leads to activation of the PERK/eIF2α/ATF4/ATF3 pathway. Inhibiting PERK or knockdown of ATF3 rescued FADS1 inhibition-induced ER stress and cell growth suppression, while ATF3-overexpression aggravates the FADS1 inhibition-induced cell growth suppression and leads to cell death. Metabolomic analysis revealed that FADS1 inhibition results in decreased level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response, as well as impaired biosynthesis of nucleotides, possibly accounting for the cell cycle arrest. Conclusion Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.

关键词： apolipoprotein A4   Atf3   fatty acid oxidation   gene knockout   liver metabolism   metabolic regulation   sex-dependent   transcription factor  

摘要： The liver plays essential roles in maintaining systemic glucolipid homeostasis under ever changing metabolic stressors. Metabolic dysregulation can lead to both adaptive and maladaptive changes that impact systemic physiology. Here, we examined disparate genetic and environmental metabolic stressors and identified apolipoprotein A4 (ApoA4) as a circulating protein upregulated in liver-specific KOs for carnitine palmitoyltransferase 2 and pyruvate carboxylase. We found this upregulation to be exacerbated by fasting and highfat or ketogenic diets. Unique among these models was a concomitant increase in activating transcription factor 3 (Atf3). ApoA4 expression in a sex-dependent manner. To understand the requirement of Atf3 to metabolic stress, we generated liverspecific Atf3, Cpt2 double KO mice. These experiments demonstrated the requirement for Atf3 in the induction of ApoA4 mRNA, ApoA4 protein, and serum triglycerides that hepatic Atf3 and ApoA4 in response to metabolic stress in vivo.

关键词： Muscle Biology and Physiology  

摘要： Activating Transcription Factor 3 (ATF3) is a stress-responsive gene implicated in the regulation of adaptations to challenges in cellular homeostasis. ATF3 mRNA is transiently and rapidly elevated in skeletal muscle following injury or after an acute bout of resistance or endurance exercise. Knockout of ATF3 in satellite cells enhances their activation following injury in the short term but exhausts the satellite cell pool in the long term. As a result, whole-body knockout of ATF3 impairs skeletal muscle adaptations to exercise training. However, the role of myocyte-specific ATF3 in regulating skeletal muscle cell phenotype remains unclear. In this study, we aimed to investigate whether ATF3 expression is required to maintain normal muscle fiber morphology and if it is sufficient to promote myotube hypertrophy. We induced a skeletal muscle cell-specific knockout of ATF3 using systemic delivery of MyoAAV-HSA-Cre (ATF3-KO; n = 20) or MyoAAV-HSA-EV (EV; n = 15) and harvested the diaphragm for fiber type and cross-sectional area measurements. Knockout of ATF3 was confirmed by genotyping 12–16 weeks post-injection. For the overexpression studies, C2C12 myoblasts were transfected with either a mouse ATF3 expression plasmid (ATF3-OE) or a control plasmid (EV), differentiated into myotubes, and their cell morphology was examined, using myosin heavy chain staining, 5 days post-differentiation. Our analysis showed a significant decrease in the percentage of type IIa fibers (EV: 64 ± 14%, ATF3-KO: 52 ± 18%; p = 0.047) and a corresponding increase in IIb/x fibers (EV: 26 ± 10%, ATF3-KO: 39 ± 21%; p = 0.039), with no significant change in type I fibers (EV: 10 ± 7.3%, ATF3-KO: 9.0 ± 6.8%; p = 0.65). However, there were no significant differences between groups in Feret’s diameter of fibers type I (EV: 37.0 ± 7.1 µm, ATF3-KO: 39.7 ± 7.2 µm; p = 0.30), IIa (EV: 40.3 ± 1.4 µm, ATF3-KO: 39.2 ± 3.3 µm; p = 0.22), and IIb/x (EV: 35.0 ± 5.3 µm, ATF3-KO: 34.3 ± 5.1 µm; p = 0.70) or the

关键词： epigenetics regulation   lipid metabolism   mTORC1 signaling  

摘要： Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and a major contributor to cancer-related mortality globally. Central to its pathogenesis is the dysregulation of lipid metabolism in hepatocytes, leading to abnormal lipid accumulation. Our bioinformatics analysis has identified the histone acetyltransferase complex subunit VPS72 as being associated with HCC, yet the precise molecular mechanisms through which VPS72 contributes to hepatocarcinogenesis remain poorly understood. Our analysis of extensive HCC patient cohorts identifies a significant proportion with VPS72 copy number gains, which are strongly linked to adverse prognostic outcomes. By integrating RNA-Seq, ChIP-Seq, ATAC-seq, and experimental validation, we show that VPS72 overexpression activates mTORC1 signaling, subsequently promoting lipid synthesis and driving HCC progression. We further uncover that VPS72 modulates the epigenetic landscape by enhancing DNA methylation at the ATF3 promoter, resulting in ATF3 repression and subsequent activation of mTORC1. This study elucidates a novel regulatory axis that links dysregulated lipid metabolism with HCC progression, highlighting potential epigenetic and metabolic targets for therapeutic intervention.

关键词： nerve injury   nerve regeneration   ATF3   cleaved caspase 3   c-Jun   apoptosis   Hspb1   Vra1  

摘要： Introduction The rat Vra1 locus, containing glutathione S-transferase alpha 4 (Gsta4), regulates the degeneration of central nervous system (CNS) neurons in toxin-, protein-, and injury-based models. We hypothesize that Piebald Virol Glaxo.1AV1 (PVG) alleles in Vra1 confer protection and increased axonal outgrowth after peripheral nerve injury and *** DA rats (n = 14) and DA rats with PVG alleles in the Vra1 locus (***1, n = 14) were subjected to sciatic nerve transection and immediate repair. After 6 days, axonal outgrowth and protein and gene expression were analyzed in injured and uninjured nerves and dorsal root ganglia (DRG).Results No differences in axonal outgrowth were observed between strains, but the number of apoptotic Schwann cells in the injured distal nerve end was higher in ***1 than in DA rats (p = 0.003). In both strains, gene- and protein expression of activating transcription factor 3 (ATF3) and 27-kDa heat shock protein (HSP27, i.e., Hspb1) were increased in injured vs. uninjured DRG. In ***1 rats, Gsta4 gene expression was lower in injured vs. uninjured DRG (p = 0.043) but higher than in DA rats in injured nerves (p = 0.008) and injured DRG (p = 0.008). ***1 had higher gene expression of Atf3 (p = 0.016) and caspase 3 (p = 0.032) in injured nerves than DA *** Results highlight the complexity of nerve injury and repair, supporting further investigation of Gsta4 in nerve regeneration.