Research Articles
Endogenous plasma resuspension of peripheral blood mononuclear cells prevents preparative-associated stress that modifies polyA-enriched RNA responses to subsequent acute stressors
Dongyang Li1,2, Karina Al-Dahleh1,2, Daniel A Murphy2,3, Sonya Georgieva1, Nik Matthews4 and Claire L Shovlin1,2,5,*
INTRODUCTION Cells are impacted by complex and co-occurring stresses throughout a life-course. Our goal was to generate physiologically relevant models of acute cellular stress, initially in relation to 3’ untranslated
Neuroglobin-enriched secretome provides neuroprotection against hydrogen peroxide and mitochondrial toxin-induced cellular stress
Giovanna Bastari1,a, Virginia Solar Fernandez1,2,a, Maurizio Muzzi3,4, Sandra Moreno3,5, Maria Marino1,5 and Marco Fiocchetti1,5
INTRODUCTION Cellular response to stress relies on evolutionary conserved mechanisms aimed at maintaining homeostasis and facilitating adaptation to new cellular environments 1. Under stressful conditions, post-mitotic neurons are hardly replaced.
Stress granules formation in HEI-OC1 auditory cells and in H4 human neuroglioma cells secondary to cisplatin exposure
Hebatallah Abdelrasol1,a, Avika Chopra1,a, Liana Shvachiy1, Dirk Beutner2, Tiago F Outeiro1,3,4,5,* and Cristian Setz2,1,*
INTRODUCTION Cellular stress is an inherent and inevitable aspect of cell physiology, prompting cells to adapt to environmental changes. Among the distinctive intracellular adaptive responses that have been characterized in
Dynamics of cell membrane lesions and adaptive conductance under the electrical stress
Mantas Silkunas, Olga N Pakhomova, Giedre Silkuniene and Andrei G. Pakhomov
Exceeding physiological limits of the cell membrane potential compromises structural integrity, enabling the passage of normally impermeant solutes and disrupting cell function. Electropermeabilization has been studied extensively at the cellular scale, but not at the individual membrane lesion level. We employed fast total internal reflection fluorescence (TIRF) imaging of Ca2+ entry transients to discern individual lesions in a hyperpolarized cell membrane and characterize their focality, thresholds, electrical conductance, and the lifecycle. A diffuse and momentary membrane permeabilization without a distinct pore formation was observed already at a -100 mV threshold. Polarizing down to -200 mV created focal pores with a low 50- to 300-pS conductance, which disappeared instantly once the hyperpolarization was removed. Charging to - 240 mV created high-conductance (> 1 nS) pores which persisted for seconds even at zero membrane potential. With (...)
MiR-200c reprograms fibroblasts to recapitulate the phenotype of CAFs in breast cancer progression
Zhao Lin1, Megan E. Roche1, Víctor Díaz-Barros1, Marina Domingo-Vidal2, Diana Whitaker-Menezes1, Madalina Tuluc3, Guldeep Uppal3, Jaime Caro4, Joseph M. Curry5 and Ubaldo Martinez-Outschoorn1
Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces (...)
Chromatin assembly factor-1 preserves genome stability in ctf4∆ cells by promoting sister chromatid cohesion
Nagham Ghaddar1, Pierre Luciano1, Vincent Géli1, and Yves Corda1,*
Chromatin assembly and the establishment of sister chromatid cohesion are intimately connected to the progression of DNA replication forks. Here we examined the genetic interaction between the heterotrimeric chromatin assembly factor-1 (CAF-1), a central component of chromatin assembly during replication, and the core replisome component Ctf4. We find that CAF-1 deficient cells as well as cells affected in newly-synthesized H3-H4 histones deposition during DNA replication exhibit a severe negative growth with ctf4∆ mutant. We dissected the role of CAF-1 in the maintenance of genome stability in ctf4∆ yeast cells. In the absence of CTF4, CAF-1 is essential for viability in cells experiencing replication problems, in cells lacking functional S-phase checkpoint or functional spindle checkpoint, and in cells lacking DNA repair pathways involving homologous recombination. We present evidence that CAF-1 affects cohesin association to chromatin in a (...)
CRISPR-activation screen identified potassium channels for protection against mycotoxins through cell cycle progression and mitochondrial function
Yulong Tang1,4, Simeng Liao1, Zhuyuan Nie1,2, Guangwei Kuang3, Chunxiao Ji2, Dan Wan1, Liuqin He1, Fengna Li1, Xiangfeng Kong1, Kai Zhan4, Bie Tan2, Xin Wu1 and Yulong Yin1,2
Zearalenone (ZEA) exposure has carcinogenic effects on human and animal health by exhibiting intestinal, hepatic, and renal toxicity. At present, the underlying mechanisms on how ZEA induces apoptosis and damage to tissues still remain unclear. In this study, we aimed to identify genes that modulate the cellular response to ZEA using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening, and further validate novel gene functions to elucidate molecular mechanisms underlying particular biological processes in vivo and in vitro. Two ZEA-resistant cell lines, designated Ov-KCNJ4 and Ov-KCNJ12, were yielded by CRISPR activation screening which had significant changes in ZEA resistance and growth rates. Results showed that ZEA could interact with the cell membrane proteins (...)
Macrolide antibiotics activate the integrated stress response and promote tumor proliferation
Xin Yu1,#, Ai-Ling Tian2,3,4,5,#, Ping Wang6,#, Juanjuan Li1, Juan Wu7, Bei Li7, Zhou Liu1, Siqing Liu1, Zhijie Gao1, Si Sun8, Shengrong Sun1, Yi Tu1 and Qi Wu9
Macrolide antibiotics are widely used antibacterial agents that are associated with autophagy inhibition. This study aimed to investigate the association between macrolide antibiotics and malignant tumors, as well as the effect on autophagy, reactive oxygen species (ROS) accumulation and integrated stress response (ISR). The meta-analysis indicated a modestly higher risk of cancer in macrolide antibiotic ever-users compared to non-users. Further experiments showed that macrolides block autophagic flux by inhibiting lysosomal acidification. Additionally, azithromycin, a representative macrolide antibiotic, induced the accumulation of ROS, and stimulated the ISR and the activation of transcription factor EB (TFEB) and TFE3 in a ROS-dependent manner. Finally, animal experiments confirmed that azithromycin promoted tumor progression in vivo, which (...)