Multiple Signal Transduction Pathways Research Articles

Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity.

The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity-driven tumors.

The dynamic organelle primary cilia: emerging roles in organ fibrosis.

Primary cilia, the antenna-like organelles on most mammalian cells, host key components of multiple morphogen signal transduction pathways. Mutations in genes responsible for primary cilia assembly and function generally result in pathological conditions known as ciliopathies, which underlie several diseases, including various forms of fibrosis. Primary cilia modulate cellular responses to extracellular cues, including TGF-β and morphogens, such as Hedgehog. Aberrant morphogen signaling is recognized as essential for the transition of mesenchymal progenitor cells to myofibroblasts, the key step in fibrosis. This article aims to provide a critical overview of recent developments and insights in primary cilia biology relevant to fibrosis. Several studies have highlighted the association of altered primary cilia with various forms of fibrosis. In a rather complex manner, the presence of primary cilia seems to be required for initiation of myofibroblast transition, whereas its loss promotes myofibroblast transition at a later stage. Recent evidence also suggested that noncanonical functions of ciliary transport proteins may influence, such cellular transitions independently of primary cilia. The possibility of opposing signaling regulations being topologically separated between primary cilia and plasma membrane could also be critical for fibrosis. Recent progress in the field suggests that primary cilia are critical mediators of the pathogenesis of fibrosis. Understanding the potential role of primary cilia in fibrosis and the underlying mechanisms may pave the way for entirely new approaches for fibrosis prevention and treatment of SSc.

Molecular mechanisms and signaling pathways involved in immunopathological events of COVID-19

Introduction: COVID-19, a novel coronavirus that causes severe acute respiratory syndrome (SARS-CoV-2), is currently regarded as the most serious viral disease. During corona infection, viruses bind to host proteins and employ a variety of cellular pathways for their own purposes. Cell signaling is important for the regulation of cellular function. SARS-CoV-2 infection alters multiple signal transduction pathways that are critical for cell survival. The virus causes a severe and prolonged period of hypercytokinemia with misusing of these signaling cascades. Hyperactivation of the host immune system after infection with SARS-CoV-2 is the main cause of death in COVID-19 patients. Thus, to develop effective therapeutic approaches, it is necessary to first understand the problem and the underlying molecular pathways implicated in host immunological function/dysfunction. A number of intracellular signaling cascades have been implicated in infected cell pathways, including MAPK pathway, NF-κB pathway, JAK–STAT signaling pathway, PI3K/AKT/mTOR pathway and TLRI signaling cascades. Here, we have presented the molecular insights on the potential mechanisms involved in immunopathological events of COVID-19.

Peroxiredoxin 1 Interacts with TBK1/IKKε and Negatively Regulates Pseudorabies Virus Propagation by Promoting Innate Immunity.

Peroxiredoxin 1 (PRDX1) is a cellular antioxidant enzyme that is crucial for diverse fundamental biological processes, such as autophagy, inflammation, and carcinogenesis. However, molecular mechanisms underpinning its diverse roles are not well understood. Here, we report that PRDX1 positively regulates interferon (IFN) induction and that pseudorabies virus (PRV) targets PRDX1 to evade IFN induction. PRV UL13 encodes a serine/threonine kinase important for PRV infection, although its biological function remains obscure. We identified PRDX1 as a UL13-interacting protein. Virological and biochemical assays demonstrate that PRDX1 promotes IFN induction by interacting with TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε). Conversely, UL13 accelerates PRDX1 degradation via the ubiquitin-proteosome pathway in a kinase-dependent manner. In doing so, PRV inhibits IFN induction during productive infection, which requires PRDX1 expression. This study uncovers an essential role of PRDX1 in the innate immune response and reveals a new viral immune evasion strategy to counteract cellular defenses. IMPORTANCE PRV interacts with numerous cellular proteins during productive infection. Here, we demonstrated the interaction of viral protein UL13 with the antioxidant enzyme PRDX1, which functions in multiple signal transduction pathways. We found that PRDX1 participates in the type I IFN pathway by interacting with TBK1 and IKKε, thereby negatively regulating PRV propagation. However, UL13 ubiquitinates PRDX1, which routes PRDX1 into proteasomes for degradation and effectively reduces its expression. These results illuminate the fundamental role that PRDX1 plays in the IFN pathway, and they identify a potential target for the control of PRV infection.

Transcriptome and metabolome analyses of cold and darkness-induced pellicle cysts of Scrippsiella trochoidea

BackgroundDinoflagellates are a group of unicellular organisms that are a major component of aquatic eukaryotes and important contributors to marine primary production. Nevertheless, many dinoflagellates are considered harmful algal bloom (HAB) species due to their detrimental environmental and human health impacts. Cyst formation is widely perceived as an adaptive strategy of cyst-forming dinoflagellates in response to adverse environmental conditions. Dinoflagellate cysts play critical roles in bloom dynamics. However, our insight into the underlying molecular basis of encystment is still limited. To investigate the molecular processes regulating encystment in dinoflagellates, transcriptome and metabolome investigations were performed on cold and darkness-induced pellicle cysts of Scrippsiella trochoidea.ResultsNo significant transcriptional response was observed at 2 h; however, massive transcriptome and metabolome reprogramming occurred at 5 h and in pellicle cysts. The gene-to-metabolite network demonstrated that the initial transformation from vegetative cells into pellicle cysts was highly energy demanding through the activation of catabolism, including glycolysis, β-oxidation, TCA cycle and oxidative phosphorylation, to cope with cold-darkness-induced stress. However, after transformation into pellicle cysts, the metabolism was greatly reduced, and various sugars, polyunsaturated fatty acids and amino acids accumulated to prolong survival. The identification of 56 differentially expressed genes (DEGs) related to signal transduction indicated that S. trochoidea received a cold-darkness signal that activated multiple signal transduction pathways, leading to encystment. The elevated expression of genes encoding enzymes involved in ROS stress suggested that pellicle cysts respond to increased oxidative stress. Several cell cycle-related genes were repressed. Intriguingly, 11 DEGs associated with sexual reproduction suggested that pellicle cysts (or some portion thereof) may be a product of sexual reproduction.ConclusionsThis study provides the first transcriptome and metabolome analyses conducted during the encystment of S. trochoidea, an event that requires complex regulatory mechanisms and impacts on population dynamics. The results reveal comprehensive molecular regulatory processes underlying life cycle regulation in dinoflagellates involving signal transduction, gene expression and metabolite profile, which will improve our ability to understand and monitor dinoflagellate blooms.

ATM-Mediated Mitochondrial Radiation Responses of Human Fibroblasts.

Ataxia telangiectasia (AT) is characterized by extreme sensitivity to ionizing radiation. The gene mutated in AT, Ataxia Telangiectasia Mutated (ATM), has serine/threonine protein kinase activity and mediates the activation of multiple signal transduction pathways involved in the processing of DNA double-strand breaks. Reactive oxygen species (ROS) created as a byproduct of the mitochondria’s oxidative phosphorylation (OXPHOS) has been proposed to be the source of intracellular ROS. Mitochondria are uniquely vulnerable to ROS because they are the sites of ROS generation. ROS-induced mitochondrial mutations lead to impaired mitochondrial respiration and further increase the likelihood of ROS generation, establishing a vicious cycle of further ROS production and mitochondrial damage. AT patients and ATM-deficient mice display intrinsic mitochondrial dysfunction and exhibit constitutive elevations in ROS levels. ATM plays a critical role in maintaining cellular redox homeostasis. However, the precise mechanism of ATM-mediated mitochondrial antioxidants remains unclear. The aim of this review paper is to introduce our current research surrounding the role of ATM on maintaining cellular redox control in human fibroblasts. ATM-mediated signal transduction is important in the mitochondrial radiation response. Perturbation of mitochondrial redox control elevates ROS which are key mediators in the development of cancer by many mechanisms, including ROS-mediated genomic instability, tumor microenvironment formation, and chronic inflammation.

CHK Methylation Is Elevated in Colon Cancer Cells and Contributes to the Oncogenic Properties.

Src is an important oncogene that plays key roles in multiple signal transduction pathways. Csk-homologous kinase (CHK) is a kinase whose molecular roles are largely uncharacterized. We previously reported expression of CHK in normal human colon cells, and decreased levels of CHK protein in colon cancer cells leads to the activation of Src (Zhu et al., 2008). However, how CHK protein expression is downregulated in colon cancer cells has been unknown. We report herein that CHK mRNA was decreased in colon cancer cells as compared to normal colon cells, and similarly in human tissues of normal colon and colon cancer. Increased levels of DNA methylation at promotor CpG islands of CHK gene were observed in colon cancer cells and human colon cancer tissues as compared to their normal healthy counterparts. Increased levels of DNA methyltransferases (DNMTs) were also observed in colon cancer cells and tissues. DNA methylation and decreased expression of CHK mRNA were inhibited by DNMT inhibitor 5-Aza-CdR. Cell proliferation, colony growth, wound healing, and Matrigel invasion were all decreased in the presence of 5-Aza-CdR. These results suggest that increased levels of DNA methylation, possibly induced by enhanced levels of DNMT, leads to decreased expression of CHK mRNA and CHK protein, promoting increased oncogenic properties in colon cancer cells.

Role of Signal Transducing Adaptor Protein (STAP) Family in Chronic Myelogenous Leukemia

Role of Signal Transducing Adaptor Protein (STAP) Family in Chronic Myelogenous Leukemia

Epigenetic silencing of ZBTB28 promotes renal cell carcinogenesis.

Zinc finger and BTB domain-containing protein 28 (ZBTB28) is a potential tumor suppressor for some cancers. However, its epigenetic regulation and functions in renal cell carcinoma (RCC) remain to be elucidated. The expression of ZBTB28 mRNA was analyzed by semi-quantitative reverse transcription polymerase chain reaction (PCR) in nine RCC cell lines and normal kidney tissues. Methylation status of ZBTB28 promoter was assessed by methylation-specific PCR in RCC cell lines, primary RCC, tumors and adjacent tissues. The involvement of ZBTB28 in cell proliferation and migration was investigated. ZBTB28 promoter was hypermethylated in 88.9% (8/9) of RCC cell lines with reduced ZBTB28 mRNA expression, and could be reversed by DNA methyltransferase inhibitors. The methylation of ZBTB28 promoter was detected in 73.5% (36/49) of primary RCC tissues, compared with 7.1% (1/14) in normal tissues. Overexpression of ZBTB28 significantly inhibited RCC cell proliferation and migration, and induced apoptosis. Further analyses revealed that ZBTB28 upregulation could inhibit multiple oncogenic signaling transduction pathways. ZBTB28 is frequently silenced by promoter methylation in RCC pathogenesis and functions as a novel tumor suppressive gene. ZBTB28 may be a potential target for the development of RCC therapeutic strategies.

Four-and-a-half LIM domain protein 2 (FHL2) deficiency protects mice from diet-induced obesity and high FHL2 expression marks human obesity

ObjectiveFour-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In humans, methylation and expression of the FHL2 gene increases with age, and high FHL2 expression is associated with increased body weight in humans and mice. This led us to hypothesize that FHL2 is a determinant of diet-induced obesity. MethodsFHL2-deficient (FHL2−/−) and wild type male mice were fed a high-fat diet. Metabolic phenotyping of these mice, as well as transcriptional analysis of key metabolic tissues was performed. Correlation of the expression of FHL2 and relevant genes was assessed in datasets from white adipose tissue of individuals with and without obesity. ResultsFHL2 Deficiency protects mice from high-fat diet-induced weight gain, whereas glucose handling is normal. We observed enhanced energy expenditure, which may be explained by a combination of changes in multiple tissues; mild activation of brown adipose tissue with increased fatty acid uptake, increased cardiac glucose uptake and browning of white adipose tissue. Corroborating our findings in mice, expression of FHL2 in human white adipose tissue positively correlates with obesity and negatively with expression of browning-associated genes. ConclusionOur results position FHL2 as a novel regulator of obesity and energy expenditure in mice and human. Given that FHL2 expression increases during aging, we now show that low FHL2 expression associates with a healthy metabolic state.

Expression profiling and functional characterization of the duplicated Oxr1b gene in zebrafish

Oxidation Resistance Gene 1 (OXR1) is a conserved gene family involved in protecting various species against oxidative stress. The zebrafish expresses a pair of OXR1 paralogs (i.e., oxr1a and oxr1b). Our previous work has revealed the importance of oxr1a in regulating antioxidant defenses during oxidative stress, but the role of oxr1b is remains unknown. Herein we reported the spatial-temporal expression of oxr1b and revealed its function through reverse genetics. The results showed that, as with oxr1a, oxr1b is a typical maternal-zygotic gene. Its mRNA is mainly distributed in the eye, brain and nervous system (e.g., anterior/posterior lateral line ganglion, neuromasts and spinal cord neuron). Although oxr1a and oxr1b genes have similar expression patterns during embryonic development, the latter have higher levels at the corresponding stages. Subsequently, a viable oxr1b−/− mutant was generated by the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9) system. Oxr1b knockout caused multiple antioxidant genes (i.e., gpx4a, gpx4b, sod1 and sod3b) to be downregulated, resulting in hypersensitive to oxidative stress. Furthermore, by comparative transcriptome analysis, we found that oxr1b knockout inhibits multiple signal transduction pathways (e.g., MAPK signaling pathway, calcium signaling pathway, cAMP signaling pathway and ErbB signaling pathway) during oxidative stress, thereby suppressing early stress response and ultimately impairing the anti-apoptosis pathway. In conclusion, our findings demonstrate that the duplicated oxr1b gene has an important role in regulating the antioxidant defenses by modulating signaling transduction and early stress response during oxidative stress.

Aedes aegypti Toll pathway is induced through dsRNA sensing in endosomes

Mosquito anti-pathogen immune responses, including those controlling infection with arboviruses are regulated by multiple signal transduction pathways. While the Toll pathway is critical in the defense against arboviruses such as dengue and Zika viruses, the factors and mechanisms involved in virus recognition leading to the activation of the Toll pathway are not fully understood. In this study we evaluated the role of virus-produced double-stranded RNA (dsRNA) intermediates in mosquito immune activation by utilizing the synthetic dsRNA analog polyinosinic-polycytidylic acid (poly I:C). Poly I:C treatment of Aedes aegypti mosquitoes and Aag2 cells reduced DENV infection. Transcriptomic analyses of Aag2 cell responses to poly I:C indicated putative activation of the Toll pathway. We found that poly I:C is translocated to the endosomal compartment of Aag2 cells, and that the A. aegypti Toll 6 receptor is a putative dsRNA recognition receptor. This study elucidates the role of dsRNAs in the immune activation of non-RNAi pathways in mosquitoes.

Targeting Multiple Signal Transduction Pathways of SARS-CoV-2: Approaches to COVID-19 Therapeutic Candidates.

Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively, will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host–pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates.

Nobiletin Inhibits Inflammatory Reaction in Interleukin-1β-Stimulated Human Periodontal Ligament Cells.

The immune response in periodontal lesions is involved in the progression of periodontal disease. Therefore, it is important to find a bioactive substance that has anti-inflammatory effects in periodontal lesions. This study aimed to examine if nobiletin, which is found in the peel of citrus fruits, could inhibit inflammatory responses in interleukin (IL)-1β-stimulated human periodontal ligament cells (HPDLCs). The release of cytokines (IL-6, IL-8, CXCL10, CCL20, and CCL2) and matrix metalloproteinases (MMP-1 and MMP-3) was assessed by ELISA. The expression of cell adhesion molecules (ICAM-1and VCAM-1) and the activation of signal transduction pathways (nuclear factor (NF)-κB, mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt)) in HPDLCs were detected by Western blot analysis. Our experiments revealed that nobiletin decreased the expression of inflammatory cytokines, cell adhesion molecules, and MMPs in IL-1β-stimulated HPDLCs. Moreover, we revealed that nobiletin treatment could suppress the activation of the NF-κB, MAPKs, and Akt pathways. These findings indicate that nobiletin could inhibit inflammatory reactions in IL-1β-stimulated HPDLCs by inhibiting multiple signal transduction pathways, including NF-κB, MAPKs, and Akt.

Short chain fatty acids delay the development of hepatocellular carcinoma in HBx transgenic mice

Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The HBV encoded oncoprotein, HBx, alters the expression of host genes and the activity of multiple signal transduction pathways that contribute to the pathogenesis of HCC by multiple mechanisms independent of HBV replication. However, it is not clear which pathways are the most relevant therapeutic targets in hepatocarcinogenesis. Short chain fatty acids (SCFAs) have strong anti-inflammatory and anti-neoplastic properties, suggesting that they may block the progression of chronic liver disease (CLD) to HCC, thereby identifying the mechanisms relevant to HCC development. This hypothesis was tested in HBx transgenic (HBxTg) mice fed SCFAs. Groups of HBxTg mice were fed with SCFAs or vehicle from 6 to 9 months of age and then assessed for dysplasia, and from 9 to 12 months of age and then assessed for HCC. Livers from 12 month old mice were then analyzed for changes in gene expression by mass spectrometry-based proteomics. SCFA-fed mice had significantly fewer dysplastic and HCC nodules compared to controls at 9 and 12 months, respectively. Pathway analysis of SCFA-fed mice showed down-regulation of signaling pathways altered by HBx in human CLD and HCC, including those involved in inflammation, phosphatidylinositol 3-kinase, epidermal growth factor, and Ras. SCFA treatment promoted increased expression of the tumor suppressor, disabled homolog 2 (DAB2). DAB2 depresses Ras pathway activity, which is constitutively activated by HBx. SCFAs also reduced cell viability in HBx-transfected cell lines in a dose-dependent manner while the viability of primary human hepatocytes was unaffected. These unique findings demonstrate that SCFAs delay the pathogenesis of CLD and development of HCC, and provide insight into some of the underlying mechanisms that are relevant to pathogenesis in that they are responsive to treatment.

Use of Transcriptomic Analyses to Elucidate the Mechanism Governing Nodal Root Development in Eremochloa ophiuroides (Munro) Hack.

Centipedegrass [Eremochloa ophiuroides (Munro) Hack.] is a perennial warm-season grass that originated in China, and its speed of nodal rooting is important for lawn establishment. In our study, centipedegrass nodal rooting ability was limited by node aging. Transcriptome sequencing of nodal roots after 0, 2, 4, and 8 days of water culture was performed to investigate the molecular mechanisms of root development. GO enrichment and KEGG pathway analyses of DEGs indicated that plant hormone signal transduction and transcription factors might play important roles in centipedegrass nodal root growth. Among them, E3 ubiquitin-protein ligases participated in multiple hormone signal transduction pathways and interacted with transcription factors. Furthermore, an E3 ubiquitin protein ligase EoSINAT5 overexpressed in rice resulted in longer roots and more numerous root tips, while knockout of LOC_Os07g46560 (the homologous gene of EoSINAT5 in rice) resulted in shorter roots and fewer root tips. These results indicated that EoSINAT5 and its homologous gene are able to promote nodal root development. This research presents the transcriptomic analyses of centipedegrass nodal roots, and may contribute to elucidating the mechanism governing the development of nodal roots and facilitates the use of molecular breeding in improving rooting ability.

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear.Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients.Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR).Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis.Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway.

Overexpression of ZmWRKY65 transcription factor from maize confers stress resistances in transgenic Arabidopsis

Plant-specific WRKY transcription factors play important roles in regulating the expression of defense-responsive genes against pathogen attack. A multiple stress-responsive WRKY gene, ZmWRKY65, was identified in maize by screening salicylic acid (SA)-induced de novo transcriptomic sequences. The ZmWRKY65 protein was localized in the nucleus of mesophyll protoplasts. The analysis of the ZmWRKY65 promoter sequence indicated that it contains several stress-related transcriptional regulatory elements. Many environmental factors affecting the transcription of ZmWRKY65 gene, such as drought, salinity, high temperature and low temperature stress. Moreover, the transcription of ZmWRKY65 gene was also affected by the induction of defense related plant hormones such as SA and exogenous ABA. The results of seed germination and stomatal aperture assays indicated that transgenic Arabidopsis plants exhibit enhanced sensitivity to ABA and high concentrations of SA. Overexpression of ZmWRKY65 improved tolerance to both pathogen attack and abiotic stress in transgenic Arabidopsis plants and activated several stress-related genes such as RD29A, ERD10, and STZ as well as pathogenesis-related (PR) genes such as PR1, PR2 and PR5; these genes are involved in resistance to abiotic and biotic stresses in Arabidopsis. Together, this evidence implies that the ZmWRKY65 gene is involved in multiple stress signal transduction pathways.

Differential functions of TLE1 and TLE3 depending on a specific phosphorylation site

Mammalian Transducin-like enhancer of split (TLE) confer global repression of numerous target genes in conjunction with a myriad of DNA-binding repressors. These factors have a major role in the regulation of multiple signal transduction pathways. Evidence have been obtained regarding the possible role of some of these proteins in cancer. TLE3 was suggested as a marker for increased chemosensitivity from pathological studies. Here we demonstrate, using the TCGA data base, differences in expression of this gene compared to TLE1 in several cancers. In-vitro transduction of a retrovirus encoding TLE3 to A549 lung cancer cells increased paclitaxel effectivity while TLE1 introduction to these cells decreased it. While TLE1 and TLE3 share ∼80% amino acid identity, we show that mutating or reconstituting an amino-terminal phosphorylation site, which is present only in TLE1 but absent from TLE3, and is evolutionary conserved, converts the activity of TLE1 to that of TLE3 like and vice versa. We repeated these results in an adipocytes differentiation system. Our results reveal how a single phosphorylation site can confer distinct qualitative or quantitative activities on highly homologous transcriptional regulators.

Resveratrol's Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism.

Simple SummaryThe prevention and treatment of cancer is an ongoing medical challenge. In the context of personalized medicine, the well-studied polyphenol resveratrol could complement classical tumor therapy. It may affect key processes such as inflammation, angiogenesis, proliferation, metastasis, glucose metabolism, and apoptosis in various cancers because resveratrol acts as a multi-targeting agent by modulating multiple signal transduction pathways. This review article focuses on resveratrol’s ability to modify tumor glucose metabolism and its associated therapeutic capacity. Resveratrol reduces glucose uptake and glycolysis by affecting Glut1, PFK1, HIF-1α, ROS, PDH, and the CamKKB/AMPK pathway. It also inhibits cell growth, invasion, and proliferation by targeting NF-kB, Sirt1, Sirt3, LDH, PI-3K, mTOR, PKM2, R5P, G6PD, TKT, talin, and PGAM. In addition, resveratrol induces apoptosis by targeting integrin, p53, LDH, and FAK. In conclusion, resveratrol has many potentials to intervene in tumor processes if bioavailability can be increased and this natural compound can be used selectively.Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors.