FEBS Journal

Cancer initiation and progression heavily relies on microenvironmental cues derived from various components of the niche including the extracellular matrix (ECM). ECM is a complex macromolecular network that governs cell functionality. Although the two-dimensional (2D) cell culture systems provide useful information at the molecular level and preclinical testing, they could not accurately represent the in vivo matrix microenvironmental architecture. Hence, it is no surprise that researchers in the last decades have focused their efforts in establishing novel in vitro culture models that mimic tumor and tissue-specific niches and interactions...

Venom-derived peptides targeting ion channels involved in pain are regarded as a promising alternative to current, and often ineffective, chronic pain treatments. Many peptide toxins are known to specifically and potently block established therapeutic targets, among which the voltage-gated sodium and calcium channels are major contributors. Here, we report on the discovery and characterization of a novel spider toxin isolated from the crude venom of Pterinochilus murinus that shows inhibitory activity at both hNaV 1...

Ferroptosis, featuring an iron-dependent peroxidation of lipids, is a novel form of programmed cell death that may hold great potential in cancer therapy. Our study found that palmitic acid (PA) inhibited colon cancer cell viability in vitro and in vivo, in conjunction with an accumulation of reactive oxygen species (ROS) and lipid peroxidation. The ferroptosis inhibitor Ferrostatin-1 but not Z-VAD-FMK (a pan-caspase inhibitor), Necrostatin-1 (a potent necroptosis inhibitor), or CQ (a potent inhibitor of autophagy), rescued the cell death phenotype induced by PA...

Dame Carol Robinson is a professor of chemistry and Director of the Kavli Institute for Nanoscience Discovery at the University of Oxford. Carol's career in science began at the age of 16 as a lab technician at Pfizer (based in Kent), during which time she studied part-time and took evening classes to obtain a degree in chemistry. This was followed by a master's degree at the University of Swansea and a PhD at the University of Cambridge. Carol's postdoctoral training was undertaken in Peter Bennett's lab at the Department of Pathology and Microbiology, University of Bristol...

Ocular diseases are a highly heterogeneous group of phenotypes, caused by a spectrum of genetic variants and environmental factors that exhibit diverse clinical symptoms. Due to its anatomical location, structure and immune privilege, the eye is an ideal system to assess and validate novel genetic therapies. Advances in genome editing have revolutionized the field of biomedical science, enabling researchers to understand the biology behind disease mechanisms and allow treatment for several health conditions, including ocular pathologies...

Radiation resistance is the leading cause of radiotherapy failure in patients with cancer. Enhanced DNA damage repair is the main reason for cancer cells to develop resistance to radiation. Autophagy has been widely reported to be linked to increased genome stability and radiation resistance. Mitochondria are highly involved in cell response to radiotherapy. However, the autophagy subtype mitophagy has not been studied in terms of genome stability. We have previously demonstrated that mitochondrial dysfunction is the cause of radiation resistance in tumor cells...

The treatment for leishmaniasis is currently plagued by side effects such as toxicity, and the emergence of drug resistance to the available repertoire of drugs, as well as the expense of these drugs. Considering the rising concerns, we report here , the anti-leishmanial activity and mechanism of a flavone compound 4',7-dihydroxyflavone (TI 4). Four flavanoids were initially screened for anti-leishmanial activity and cytotoxicity. The results showed that the compound TI 4 exhibited higher activity and selectivity index while maintaining low cytotoxicity...

Quiescence or G0 is a reversible state in which cells cease division but retain the ability to resume proliferation. Quiescence occurs in all organisms and is essential for stem cell maintenance and tissue renewal. It is also related to chronological lifespan - the survival of post-mitotic quiescent cells over time - and thus contributes to longevity. Important questions remain regarding the mechanisms that control entry into quiescence, maintenance of quiescence, and re-entry of quiescent cells into the cell cycle...

Metabolic reprogramming is a hallmark of cancer. Several studies have shown that inactivation of Krebs cycle enzymes, such as citrate synthase (CS) and fumarate hydratase (FH), facilitates aerobic glycolysis and cancer progression. MAEL has been shown to play an oncogenic role in bladder, liver, colon and gastric cancers, but its role in breast cancer and metabolism is still unknown. Here, we demonstrated that MAEL promoted malignant behaviors and aerobic glycolysis in breast cancer cells. Mechanistically, MAEL interacted with CS/FH and HSAP8 via its MAEL domain and HMG domain, respectively, and then enhanced the binding affinity of CS/FH with HSPA8, facilitating the transport of CS/FH to the lysosome for degradation...

OsMADS29 (M29) is a crucial regulator of seed development in rice. The expression of M29 is strictly regulated at transcriptional as well as post-transcriptional levels. The MADS-box proteins are known to bind to DNA as dimers. However, in the case of M29, the dimerization also plays a vital role in its localization into the nucleus. The factor(s) that affect oligomerization and nuclear transport of MADS proteins have not yet been characterized. By using BiFC in transgenic BY-2 cell lines and Yeast-2-hybrid assay (Y2H), we show that calmodulin (CaM) interacts with M29 in a Ca2+ dependent manner...

Over 4 billion years of evolution, multiple mutations, including nucleotide substitutions, gene and genome duplications, and recombination, have established de novo genes that translate into proteins with novel properties essential for high-order cellular functions. However, molecular processes through which a protein evolutionarily acquires a novel function are mostly speculative. Recently, we have provided evidence for a potential evolutionary mechanism underlying how, in mammalian cells, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) evolved into a GTP sensor from ATP-utilizing kinase...

Autism spectrum disorders (ASD) are associated with the contribution of many prenatal risk factors; in particular, the sex hormone progestin and vitamin D receptor (VDR) are associated with gastrointestinal (GI) symptoms in ASD development, although the related mechanism remains unclear. We investigated the possible role and mechanism of progestin 17-hydroxyprogesterone caproate (17-OHPC) exposure-induced GI dysfunction and autism-like behaviors (ALB) in mouse offspring. An intestine-specific VDR deficient mouse model was established for prenatal treatment, while transplantation of hematopoietic stem cells (HSCT) with related gene manipulation were used for postnatal treatment for 17-OHPC exposure-induced GI dysfunction and ALB in mouse offspring...

The dimeric avidin family has been expanded in recent years to include many new members. All of them lack the intermonomeric Trp that plays a critical role in biotin-binding. Nevertheless, these new members of the avidins maintain the high affinity towards biotin. Additionally, all of the dimeric avidins share a very unique property: namely, the cylindrical oligomerization in the crystal structure. The newest member described here, agroavidin from the agrobacterium, Rhizobium sp. AAP43, shares their important structural features...

The development of neurological pathologies is linked to the accumulation of protein aggregates like alpha-synuclein in Parkinson's disease and tau protein in Alzheimer's disease. Mono or di ubiquitination of these molecules has been reported to stabilize aggregates and contribute to the disorders. STUB1(STIP1 Homologous and U-Box containing protein 1) is a multifunctional protein that maintains proteostasis and insulin signaling. In spinocerebellar Ataxia 16 (SCA16), an autosomal recessive neurodegenerative disease, mutations in and aggregation of STUB1 are reported...

G protein-coupled receptor 83 (GPR83) is primarily expressed in the brain and is implicated in the regulation of energy metabolism and some anxiety-related behaviors. Recently, the PCSK1N/proSAAS-derived peptide PEN, the procholecystokinin-derived peptide proCCK56-63, and family with sequence similarity 237 member A (FAM237A) were all reported as efficient agonists of GPR83. However, these results have not yet been reproduced by other laboratories and thus GPR83 is still officially an orphan receptor. The peptide PEN and proCCK56-63 share sequence similarity; however, they are completely different from FAM237A...

Orphan nuclear receptor estrogen-related receptor alpha (ERRα) is an important regulator of energy metabolism, whereas its hyperactivation in breast cancer has been shown to regulate cell migration, proliferation, and tumour development. These findings suggest a fine balance in the status of ERRα in regulating metabolic homeostasis or promoting cancer progression. In this issue, Brindisi et al. have shown that ERRα is endogenously activated by cholesterol and caused breast cancer aggressiveness...

Hypoxia Inducible Factor 1, a heterodimer of alpha (HIF-1α) and beta (HIF-1β or ARNT) subunits, is a major regulator of the transcriptional response to hypoxia. However, HIF-1α, the oxygen-regulated subunit, also exerts non-transcriptional functions through interaction with proteins other than ARNT. We have previously shown that the subcellular localization and protein interactions of HIF-1α are controlled by ERK-mediated phosphorylation at Ser641/643. When HIF-1α is modified at these sites, it is nuclear, binds to ARNT, interacts with NPM1, and activates transcription of hypoxia-target genes...

Skin serves as a barrier to protect our body from injury, pathogens and trans-epidermal water loss. It is the only tissue directly exposed to oxygen besides lungs. Air exposure is an essential step of in vitro generation skin graft. However, the role of oxygen in this process remains hitherto unclear. Teshima et al. unveiled the impact of the hypoxia-inducible factor (HIF) pathway on epidermal differentiation in three-dimensional skin models. The authors of this work describe how air-lifting of organotypic epidermal cultures impairs HIFs activity, leading to a proper terminal differentiation of keratinocytes and stratification...

Acid-β-glucosidase (GCase, EC 3.2.1.45), the lysosomal enzyme which hydrolyzes the simple glycosphingolipid, glucosylceramide (GlcCer), is encoded by the GBA1 gene. Biallelic mutations in GBA1 cause the human inherited metabolic disorder, Gaucher disease (GD), in which GlcCer accumulates, while heterozygous GBA1 mutations are the highest genetic risk factor for Parkinson's disease (PD). Recombinant GCase (e.g., Cerezyme®) is produced for use in enzyme replacement therapy for GD and is largely successful in relieving disease symptoms, except for the neurological symptoms observed in a subset of patients...

Glutathione transferases (GSTs) are a class of phase II detoxifying enzymes catalyzing the conjugation of glutathione (GSH) to endogenous and exogenous electrophilic molecules, microsomal glutathione transferase 1 (MGST1) being one of its key members. MGST1 forms a homotrimer displaying third-of-the-sites-reactivity and up to 30-fold activation through modification of its Cys-49 residue. It has been shown that the steady-state behavior of the enzyme at 5 °C can be accounted for by its pre-steady-state behavior if the presence of a natively activated subpopulation (approximately 10 %) is assumed...