Advances in biological regulation最新文献

During evolution, living cells have developed sophisticated molecular and physiological processes to cope with a variety of stressors. These mechanisms, which collectively constitute the Environmental Stress Response, involve the activation/repression of hundreds of genes that are regulated to respond rapidly and effectively to protect the cell. The main stressors include sudden increases in environmental temperature and osmolarity, exposure to heavy metals, nutrient limitation, ROS accumulation, and protein-damaging events. The growth stages of the yeast S. cerevisiae proceed from the exponential to the diauxic phase, finally reaching the stationary phase. It is in this latter phase that the main stressor events are more active. In the present work, we aim to understand whether the responses evoked by the sudden onset of a stressor, like what happens to cells going through the stationary phase, would be different or similar to those induced by a gradual increase in the same stimulus. To this aim, we studied the expression of the HSP12 gene of the HSP family of proteins, typically induced by stress conditions, with a focus on the role of chromatin in this regulation. Analyses of nucleosome occupancy and three-dimensional chromatin conformation suggest the activation of a different response pathway upon a sudden vs a gradual onset of a stress stimulus. Here we show that it is the three-dimensional chromatin structure of HSP12, rather than nucleosome remodeling, that becomes altered in HSP12 transcription during the stationary phase.

Several studies over the last decade demonstrate the recruitment of immune cells, increased inflammatory cytokines, and chemokine in patients with metabolic diseases, including heart failure, parenchymal inflammation, obesity, tuberculosis, and diabetes mellitus. Metabolic rewiring of immune cells is associated with the severity and prevalence of these diseases. The risk of developing COVID-19/SARS-CoV-2 infection increases in patients with metabolic dysfunction (heart failure, diabetes mellitus, and obesity). Several etiologies, including fatigue, dyspnea, and dizziness, persist even months after COVID-19 infection, commonly known as Post-Acute Sequelae of CoV-2 (PASC) or long COVID. A chronic inflammatory state and metabolic dysfunction are the factors that contribute to long COVID. Here, this study explores the potential link between pathogenic metabolic and immune alterations across different organ systems that could underlie COVID-19 and PASC. These interactions could be utilized for targeted future therapeutic approaches.

Obsessive Compulsive Disorder (OCD) is a mental health condition still classified and diagnosed with subjective interview-based assessments and which molecular clues have not completely been elucidated. We have recently identified a new regulator of anxiety and OCD-like behavior called Immuno-moodulin (IMOOD) and, here, we report that IMOOD gene promoter is differentially methylated in OCD subjects when compared to genomic material collected from healthy controls and this alteration is significantly correlated with the increased expression of the gene in OCD. We also demonstrated that IMOOD promoter can form G-quadruplexes and we suggest that, in homeostatic conditions, these structures could evoke DNA-methylation silencing the gene, whereas in pathological conditions, like OCD, could induce gene expression making the promoter more accessible to transcriptional factors. We here thus further suggest IMOOD as a new biomarker for OCD and also hypothesize new mechanisms of gene regulation.

Acute myeloid leukemia is a heterogeneous hematopoietic malignancy, characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells, with poor outcomes.

The internal tandem duplication (ITD) mutation of the Fms-like receptor tyrosine kinase 3 (FLT3) (FLT3-ITD) represents the most common genetic alteration in AML, detected in approximately 30% of AML patients, and is associated with high leukemic burden and poor prognosis. Therefore, this kinase has been regarded as an attractive druggable target for the treatment of FLT3-ITD AML, and selective small molecule inhibitors, such as quizartinib, have been identified and trialled. However, clinical outcomes have been disappointing so far due to poor remission rates, also because of acquired resistance. A strategy to overcome resistance is to combine FLT3 inhibitors with other targeted therapies. In this study, we investigated the preclinical efficacy of the combination of quizartinib with the pan PI3K inhibitor BAY-806946 in FLT3-ITD cell lines and primary cells from AML patients. We show here that BAY-806946 enhanced quizartinib cytotoxicity and, most importantly, that this combination increases the ability of quizartinib to kill CD34⁺ CD38⁻leukemia stem cells, whilst sparing normal hematopoietic stem cells. Because constitutively active FLT3 receptor tyrosine kinase is known to boost aberrant PI3K signaling, the increased sensitivity of primary cells to the above combination can be the mechanistic results of the disruption of signaling by vertical inhibition.

Highly mutable influenza is successfully countered based on individual susceptibility and similar precision-like medicine approach should be effective against SARS-COV-2. Among predictive markers to bring precision medicine to COVID-19, circulating ACE2 has potential features being upregulated in both severe COVID-19 and predisposing comorbidities. Spike SARS-CoVs were shown to induce ADAM17-mediated shedding of enzymatic active ACE2, thus accounting for its increased activity that has also been suggested to induce positive feedback loops leading to COVID-19-like manifestations. For this reason, pre-existing ACE2 activity and inhibition of ACE2/ADAM17 zinc-metalloproteases through zinc chelating agents have been proposed to predict COVID-19 outcome before infection and to protect from COVID-19, respectively. Since most diagnostic laboratories are not equipped for enzymatic activity determination, other potential predictive markers of disease progression exploitable by diagnostic laboratories were explored.

Concentrations of circulating albumin, zinc, ACE2 protein and its activity were investigated in healthy, diabetic (COVID-19-susceptible) and SARS-CoV-2-negative COVID-19 individuals.

ACE2 both protein levels and activity significantly increased in COVID-19 and diabetic patients. Abnormal high levels of ACE2 characterised a subgroup (16–19%) of diabetics, while COVID-19 patients were characterised by significantly higher zinc/albumin ratios, pointing to a relative increase of albumin-unbound zinc species, such as free zinc ones.

Data on circulating ACE2 levels are in line with the hypothesis that they can drive susceptibility to COVID-19 and elevated zinc/albumin ratios support the therapeutic use of zinc chelating inhibitors of ACE2/ADAM17 zinc-metalloproteases in a targeted therapy for COVID-19.

The 5′ untranslated regions (UTRs) in messenger RNAs (mRNAs) play an important role in the regulation of protein synthesis. We had previously identified a group of mRNAs that includes human semaphorin 7A (SEMA7A) whose translation is upregulated by the Erk/p90S6K pathway in human eosinophils, with a potential negative impact in asthma and airway inflammation. In the current study, we aimed to find a common 5′UTR regulatory cis-element, and determine its impact on protein synthesis. We identified a common and conserved 5′UTR motif GGCTG—[(C/G)T(C/G)]_n—GCC that was present in this group of mRNAs. Mutations of the first two GG bases in this motif in SEMA7A 5′UTR led to a complete loss of S6K activity dependence for maximal translation. In conclusion, the newly identified 5′UTR motif present in SEMA7A has a critical role in regulating S6K-dependent protein synthesis.

Hydrogen peroxide (H₂O₂) is one of reactive oxygen species (ROS) and promotes malignant properties of cancer cells. Lysophosphatidic acid (LPA) signaling via LPA receptor (LPA₁ to LPA₆) regulates a variety of cellular functions, such as cell growth, migration and differentiation. This study aimed to evaluate the effects of LPA receptors on the cell motility and survival to anticancer drugs by H₂O₂ in colon cancer DLD-1 cells. To obtain H₂O₂ treated (DLD- H₂O₂) cells, cells were maintained in culture medium containing H₂O₂ (60 μM) for 2 months. LPAR2 and LPAR4 gene expressions were markedly elevated in DLD-H₂O₂ cells. The cell motility of DLD-H₂O₂ cells was significantly lower than that of DLD-1 cells. DLD-H₂O₂ cell motility was suppressed by LPA₂ knockdown and stimulated by LPA₄ knockdown. The cell survival rates to fluorouracil (5-FU), irinotecan (CPT-11) and oxaliplatin (L-OHP) of DLD-H₂O₂ cells were significantly higher than those of DLD-1 cells. The cell survival rate to 5-FU of DLD-H₂O₂ cells was decreased by LPA₂ knockdown. Conversely, LPA₄ knockdown enhanced the cell survival rate to 5-FU of DLD-H₂O₂ cells. In the tumor microenvironment, high levels of H₂O₂ production are observed under hypoxic conditions. The cell survival rate to 5-FU of DLD-H₂O₂ cells cultured at 1% O₂ was significantly higher than that of DLD-1 cells cultured at 1% O₂, correlating with LPAR2 gene expression. The present results suggest that the induction of LPA receptor-mediated signaling plays an important role in regulating cellular functions of DLD-1 cells treated with H₂O₂.

Cellular functions are regulated by signal transduction pathway networks consisting of protein-modifying enzymes that control the activity of many downstream proteins. Protein kinases and phosphatases regulate gene expression by reversible phosphorylation of transcriptional factors, which are their direct substrates. Casein kinase II (CK2) is a serine/threonine kinase that phosphorylates a large number of proteins that have critical roles in cellular proliferation, metabolism and survival. Altered function of CK2 has been associated with malignant transformation, immunological disorders and other types of diseases. Protein phosphatase 1 (PP1) is a serine/threonine phosphatase, which regulates the phosphorylation status of many proteins that are essential for cellular functions. IKAROS is a DNA-binding protein, which functions as a regulator of gene transcription in hematopoietic cells. CK2 directly phosphorylates IKAROS at multiple phosphosites which determines IKAROS activity as a regulator of gene expression. PP1 binds to IKAROS via the PP1-consensus recognition site and dephosphorylates serine/threonine residues that are phosphorylated by CK2. Thus, the interplay between CK2 and PP1 signaling pathways have opposing effects on the phosphorylation status of their mutual substrate – IKAROS. This review summarizes the effects of CK2 and PP1 on IKAROS role in regulation of gene expression and its function as a tumor suppressor in leukemia.

Diacylglycerol (DAG) and phosphatidic acid (PtdOH) play important roles in a variety of signaling cascades (Carrasco and Merida, 2007; Stace and Ktistakis, 2006). Therefore, the physiological roles and regulatory mechanisms controlling the levels of these lipids are important. One class of enzymes capable of coordinating the levels of these two lipids are the diacylglycerol kinases (DGKs). DGKs catalyze the transfer of the γ-phosphate of ATP to the hydroxyl group of DAG which generates PtdOH(Merida et al., 2008; Sakane et al., 2007). As DGKs reciprocally modulate the relative levels of these two signaling lipids, it is not surprising that there is increasing interest in understanding the mechanism underlying the catalysis and regulation of these kinases. While post-translational modifications (PTMs) are often involved in enzyme regulation, there is surprisingly little information regarding the PTMs on these enzymes and their roles in modulating their activity and function. In this review, we will summarize what is known about one PTM on DGKs, phosphorylation, and the possible functions of this modification.

DJ-1 has gained extensive attention after being identified in 2003 as a protein implicated in the pathogenesis of early-onset Parkinson's disease. Since then, efforts have revealed versatile DJ-1 functions in reactive oxygen species (ROS) control, transcriptional regulation, chaperone function, fertility, and cell transformation. Herein, we report a novel function of DJ-1 in actin cytoskeletal rearrangements. DJ-1 was identified as a new binding partner of Mena, a protein of the Enah/VASP family, and it promoted cancer cell migration by Mena-dependent actin polymerization and filopodia formation. These results suggest a novel molecular mechanism for DJ-1-dependent cancer cell invasion and metastasis.