Crosstalk Of Signaling Pathways Research Articles

Cell surface integrin α5ß1 clustering negatively regulates receptor tyrosine kinase signaling in colorectal cancer cells via glycogen synthase kinase 3.

As a key process within the tissue microenvironment, integrin signaling can influence cell functional responses to growth factor stimuli. We show here that clustering of integrin α5ß1 at the plasma membrane of colorectal cancer-derived epithelial cells modulates their ability to respond to stimulation by receptor tyrosine kinase (RTK)-activating growth factors EGF, NRG and HGF, through GSK3-mediated suppression of Akt pathway. We observed that integrin α5ß1 is lost from the membrane of poorly organized human colorectal tumors and that treatment with the integrin-clustering antibody P4G11 is sufficient to induce polarity in a mouse tumor xenograft model. While adding RTK growth factors (EGF, NRG and HGF) to polarized colorectal cancer cells induced invasion and loss of monolayer formation in 2D and 3D, this pathological behavior could be blocked by P4G11. Phosphorylation of ErbB family members as well as MET following EGF, NRG and HGF treatment was diminished in cells pretreated with P4G11. Focusing on EGFR, we found that blockade of integrin α5ß1 increased EGFR phosphorylation. Since activity of multiple downstream kinase pathways were altered by these various treatments, we employed computational machine learning techniques to ascertain the most important effects. Partial least-squares discriminant analysis identified GSK3 as a major regulator of EGFR pathway activities influenced by integrin α5ß1. Moreover, we used partial correlation analysis to examine signaling pathway crosstalk downstream of EGF stimulation and found that integrin α5ß1 acts as a negative regulator of the AKT signaling cascade downstream of EGFR, with GSK3 acting as a key mediator. We experimentally validated these computational inferences by confirming that blockade of GSK3 activity is sufficient to induce loss of polarity and increase of oncogenic signaling in the colonic epithelial cells.

Genome-Wide Identification and Expression Analysis of MYB Transcription Factors and Their Responses to Abiotic Stresses in Woodland Strawberry (Fragaria vesca)

Woodland strawberry (Fragaria vesca) is a diploid strawberry that is widely used as a model of cultivated octoploid strawberry (Fragaria × ananassa). It has also been used as a model for Rosaceae fruits, non-climacteric fruits, and stolons. The MYB superfamily is the largest transcription factor family in plants, and its members play important roles in plant growth and development. However, the complete MYB superfamily in woodland strawberry has not been studied. In this study, a total of 217 MYB genes were identified in woodland strawberry and classified into four groups: one 4R-MYB protein, five 3R-MYB proteins, 113 2R-MYB proteins, and 98 1R-MYB proteins. The phylogenetic relationship of each MYB subgroup was consistent in terms of intron/exon structure and conserved motif composition. The MYB genes in woodland strawberry underwent loss and expansion events during evolution. The transcriptome data revealed that most FveMYB genes are expressed in several organs, whereas 15 FveMYB genes exhibit organ-specific expression, including five genes (FveMYB101, -112, -44, and -8; FveMYB1R81) in roots, two genes (FveMYB62 and -77) in stolon tips, three genes (FveMYB99 and -35; FveMYB1R96) in open flowers, and five genes (FveMYB76 and -100; FveMYB1R4, -5, and -86) in immature fruits. During fruit ripening of woodland strawberry, the expression levels of 84 FveMYB genes were decreased, of which five genes (FveMYB4, -22, -50, and -66; FveMYB1R57) decreased more than 10-fold, whereas those 18 FveMYB genes were increased, especially FveMYB10 and FveMYB74 increased more than 30-fold. In addition, the expression levels of 36, 68, 52, and 62 FveMYB genes were altered by gibberellic acid, abscisic acid, cold, and heat treatments, respectively, and among them, several genes exhibited similar expression patterns for multiple treatments, suggesting possible roles in the crosstalk of multiple signaling pathways. This study provides candidate genes for the study of stolon formation, fruit development and ripening, and abiotic stress responses.

Crosstalk between 17β-Estradiol and TGF-β Signaling Modulates Glioblastoma Progression.

Epithelial–mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream components of 17β-estradiol (E2) and transforming growth factor β (TGF-β) signaling pathways crosstalk in estrogen-sensitive tumors. However, little is known about the interaction between the E2 and TGF-β signaling components in brain tumors. We have investigated the relationship between E2 and TGF-β signaling pathways and their effects on EMT induction in human GBM-derived cells. Here, we showed that E2 and TGF-β negatively regulated the expression of estrogen receptor α (ER-α) and Smad2/3. TGF-β induced Smad2 phosphorylation and its subsequent nuclear translocation, which E2 inhibited. Both TGF-β and E2 induced cellular processes related to EMT, such as morphological changes, actin filament reorganization, and mesenchymal markers (N-cadherin and vimentin) expression. Interestingly, we found that the co-treatment of E2 and TGF-β blocked EMT activation. Our results suggest that E2 and TGF-β signaling pathways interact through ER-α and Smad2/3 mediators in cells derived from human GBM and inhibit EMT activation induced by both factors alone.

TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis.

The complexity of intracellular signaling requires both a diversity of molecular players and the sequestration of activity to unique compartments within the cell. Recent findings on the role of liquid-liquid phase separation provide a distinct mechanism for spatial segregation of proteins to regulate signaling pathway crosstalk. Here we discover that DACT1 is induced by TGF-β and forms protein condensates in the cytoplasm to repress Wnt signaling. These condensates do not localize to any known organelles but rather exist as phase-separated proteinaceous cytoplasmic bodies. Deletion of intrinsically disordered domains within the DACT1 protein eliminates its ability to both form protein condensates and suppress Wnt signaling. Isolation and mass spectrometry analysis of these particles revealed a complex of protein machinery that sequesters Casein Kinase 2, a Wnt pathway activator. We further demonstrate that DACT1 condensates are maintained in vivo and that DACT1 is critical to breast and prostate cancer bone metastasis.

Transcriptomic Identification of Draxin-Responsive Targets During Cranial Neural Crest EMT.

Canonical Wnt signaling plays an essential role in proper craniofacial morphogenesis, at least partially due to regulation of various aspects of cranial neural crest development. In an effort to gain insight into the etiology of craniofacial abnormalities resulting from Wnt signaling and/or cranial neural crest dysfunction, we sought to identify Wnt-responsive targets during chick cranial neural crest development. To this end, we leveraged overexpression of a canonical Wnt antagonist, Draxin, in conjunction with RNA-sequencing of cranial neural crest cells that have just activated their epithelial–mesenchymal transition (EMT) program. Through differential expression analysis, gene list functional annotation, hybridization chain reaction (HCR), and quantitative reverse transcription polymerase chain reaction (RT-qPCR), we validated a novel downstream target of canonical Wnt signaling in cranial neural crest – RHOB – and identified possible signaling pathway crosstalk underlying cranial neural crest migration. The results reveal novel putative targets of canonical Wnt signaling during cranial neural crest EMT and highlight important intersections across signaling pathways involved in craniofacial development.

Crosstalk of Cancer Signaling Pathways by Cyclic Hexapeptides and Anthraquinones from Rubia cordifolia.

The anticancer activities of Rubia cordifolia and its constituents have been reported earlier, but their influence on the crosstalk of complex cancer-related signaling metabolic pathways (i.e., transcription factors; TF) has not yet been fully investigated. In this study, R. cordifolia root extract was subjected to the cancer signaling assay based bioactivity-guided fractionation, which yielded the following compounds viz., three anthraquinones, namely alizarin (1), purpurin (2), and emodin (3); two lignans, namely eudesmin (4) and compound 5; and two cyclic hexapeptides, namely deoxybouvardin RA-V (6), and a mixture of 6+9 (RA-XXI). The structures of the isolated compounds were determined by NMR spectroscopy and HRESIMS. The isolated compounds 1, 2, 3, 6, and a mixture of 6+9 were tested against a panel of luciferase reporter genes that assesses the activity of a wide-range of cancer-related signaling pathways. In addition, reference anthraquinones viz., chrysophanol (11), danthron (12), quinizarin (13), aloe-emodin (14), and α-lapachone (15) were also tested. Among the tested compounds, the cyclic hexapeptide 6 was found to be very active against several signaling pathways, notably Wnt, Myc, and Notch with IC50 values of 50, 75, and 93 ng/mL, respectively. Whereas, the anthraquinones exhibited very mild or no inhibition against these signaling pathways. Compound 6 being the most active, we tested it for stability in simulated intestinal (SIF) and gastric fluids (SGF), since the stability in biological fluid is a key short-coming of cyclic hexapeptides. The anticancer activity of 6 was found to remain unchanged before and after the treatment of simulated gastric/intestinal fluids, indicating that RA-V was stable. As a result, it could be bioavailable when orally used in therapeutics and possibly a drug candidate for cancer treatment. The mechanism for the preferential inhibition of these pathways and the possible crosstalk effect with other previously reported signaling pathways has been discussed.

Remodeling cancer stemness by collagen/fibronectin via the AKT and CDC42 signaling pathway crosstalk in glioma.

Cancer development is a complex set of proliferative progression, which arises in most cases via multistep pathways associated with various factors, including the tumor microenvironment and extracellular matrix. However, the underlying mechanisms of cancer development remain unclear and this study aimed to explore the role of extracellular matrix in glioma progression.Methods: The expression of type I collagen and fibronectin in tumor tissues from glioma patients was examined by immunofluorescence staining. The correlations between collagen/fibronectin and glioma progression were then analyzed. A 3D collagen/fibronectin cultured system was established for tumor cells culture in vitro. Quantitative, real-time PCR and western blot were used to detect PI3K/ATK and CDC42 signals associated proteins expression in glioma. We used in vitro Cell Counting Kit-8, colony formation, and tumorigenesis assays to investigate the function of PI3K/AKT and CDC42 signals associated proteins. A xenograft glioma mice model was also used to study the anticancer effects of integrin inhibitor in vivo.Results: Our study demonstrated that type I collagen and fibronectin collaborate to regulate glioma cell stemness and tumor growth. In a 3D collagen/fibronectin culture model, glioma cells acquired tumorigenic potential and revealed strengthened proliferative characteristics. More significantly, collagen/fibronectin could facilitate the activation of PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways via integrin αvβ3, eliciting sustained tumor growth and cancer relapse. Combination of the integrin signaling pathway inhibitor and the chemotherapeutic agent efficiently suppressed glioma cell proliferation and tumorigenic ability.Conclusion: We demonstrated that type I collagen and fibronectin could collaborate to promote glioma progression through PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways. Blockade of the upstream molecular integrin αvβ3 revealed improved outcome in glioma therapy, which provide new insights for eradicating tumors and reducing glioma cancer relapse.

Constitutive expression of Arabidopsis bZIP transcription factor AREB1 activates cross-signaling responses in soybean under drought and flooding stresses

Abiotic stress, such as drought and flooding, are responsible for considerable losses in grain production worldwide. Soybean, the main cultivated oilseed in the world, is sensitive to both stresses. Plant molecular mechanisms answer via crosstalk of several signaling pathways, in which particular genes can respond to different stresses. Previous studies confirmed that overexpression of transcription factor AtAREB1 confers drought tolerance in soybean. However, plants containing this gene have not yet been tested under flooding. Thus, the objective of this study was to characterize genetically modified (GM) soybean plants overexpressing AtAREB1 under drought and flooding conditions in comparison to its genetic background. Physiological and biochemical measurements were performed. In addition, the expression level of genes commonly activated under both stresses was evaluated. The results supported the role of the AtAREB1 gene in conferring tolerance to water deficit in soybeans. Furthermore, under flooding, the GM line was efficient in maintaining a higher photosynthetic rate, intrinsic efficiency in water use, and instantaneous carboxylation efficiency, resulting in higher grain yield under stress. The GM line also presented higher protein content, lower concentration of hydrogen peroxide, and lower expression levels of genes related to fermentative metabolism and alanine biosynthesis. These results indicate that in addition to drought stress, plants overexpressing AtAREB1 exhibited better performance under flooding when compared to the non-GM line, suggesting a cross-signaling response to both abiotic factors.

The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets.

Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.

Roles of Src family kinase, Ras, and mTOR signaling in intestinal epithelial homeostasis and tumorigenesis.

The turnover of intestinal epithelial cells (IECs) is relatively rapid (3‐5 days in mouse and human), and this short existence and other aspects of the homeostasis of IECs are tightly regulated by various signaling pathways including Wnt‐β‐catenin signaling. Dysregulation of IEC homeostasis likely contributes to the development of intestinal inflammation and intestinal cancer. The roles of receptor protein tyrosine kinases and their downstream signaling molecules such as Src family kinases, Ras, and mTOR in homeostatic regulation of IEC turnover have recently been evaluated. These signaling pathways have been found to promote not only the proliferation of IECs but also the differentiation of progenitor cells into secretory cell types such as goblet cells. Of note, signaling by Src family kinases, Ras, and mTOR has been shown to oppose the Wnt‐β‐catenin signaling pathway and thereby to limit the number of Lgr5+ intestinal stem cells or of Paneth cells. Such cross‐talk of signaling pathways is important not only for proper regulation of IEC homeostasis but for the development of intestinal tumors and potentially for anticancer therapy.

Cross-talk of Signaling Pathways in the Pathogenesis of Allergic Asthma and Cataract.

Allergic asthma is a chronic inflammatory disease, which involves many cellular and cellular components. Cataract is a condition that affects the transparency of the lens, which the opacity of the lens caused by any innate or acquired factor degrades its transparency or changes in color. Both of them belong to diseases induced by immune disorders or inflammation. We want to confirm the signaling pathways involved in the regulation of asthma and cataract simultaneously, and provide reference for the later related experiments. So we conducted a scoping review of many databases and searched for studies (Academic research published in Wiley, Springer and Bentham from 2000 to 2019) about the possible relationship between asthma and cataract. It was found that during the onset of asthma and cataract, Rho/Rock signaling pathway, Notch signaling pathway, Wnt/β-catenin signaling pathway, PI3K/AKT signaling pathway, JAK/STAT signaling pathway, MAPK signaling pathway, TGF-β1/Smad signaling pathway and NF-κB signaling pathway are all active, so they may have a certain correlation in pathogenesis. Asthma may be associated with cataract through the eight signaling pathways, causing inflammation or immune imbalance based on allergy that can lead to cataract. According to these studies, we speculated that the three most likely signaling pathways are PI3K/AKT, MAPK and NF-κB signaling pathway.

The Study of Sarcoma Microenvironment Heterogeneity Associated With Prognosis Based on an Immunogenomic Landscape Analysis

Microenvironment-driven tumor heterogeneity causes the limitation of immunotherapy of sarcomas. Nonetheless, systematical studies of various molecular levels can enhance the understanding of tumor microenvironment (TME) related to prognosis and provide novel insights of precision immunotherapy. Three prognostic-related TME phenotypes were identified by consensus clustering of the relative infiltration of 22 immune cells from 869 samples of sarcomas. Additionally, integrative immunogenomic analysis is applied to explore the characteristics of different TME groups. The results revealed that most of the immune cell infiltration is higher in the better prognostic group, which are more affected by lower DNA methylation levels and fewer copy number variations in the worse prognostic group. The signaling pathway crosstalk analysis suggested that the changes in the TME will cause considerable variation in the flow of information between pathways, especially when the degree of relative infiltration of immune cells is low, patient’s endocrine system may also be significantly affected. Also, the endogenous competitive network analysis indicated that several differentially expressed long non-coding RNAs (lncRNAs) associated with the prognosis or tumor recurrence of sarcoma patients affected the regulatory relationship between miRNAs and different genes when the sarcoma microenvironment changes. In summary, the significant relationship between genetic alterations and prognostic-related TME characteristics in sarcomas were determined in this study. These findings may provide new clues for the treatment of sarcomas.

LRP6 lets Merlin go in times of nutrient scarcity.

Cells take advantage of cross-talk in signaling pathways to integrate diverse signals and produce coordinated responses. In this issue of EMBO Reports, Jeong etal discover that the Wnt co-receptor, low-density lipoprotein (LDL) receptor-related protein LRP6, negatively regulates Hippo signaling by serving as a binding sink to sequester and inhibit Merlin, an activator of Hippo signaling (Jeong etal, 2020). This regulation is nutrient-responsive, likely using LRP6 O-GlcNAcylation as a molecular switch.

New Insights Into Cranial Synchondrosis Development: A Mini Review.

The synchondroses formed via endochondral ossification in the cranial base are an important growth center for the neurocranium. Abnormalities in the synchondroses affect cranial base elongation and the development of adjacent regions, including the craniofacial bones. In the central region of the cranial base, there are two synchondroses present—the intersphenoid synchondrosis and the spheno-occipital synchondrosis. These synchondroses consist of mirror image bipolar growth plates. The cross-talk of several signaling pathways, including the parathyroid hormone-like hormone (PTHLH)/parathyroid hormone-related protein (PTHrP), Indian hedgehog (Ihh), Wnt/β-catenin, and fibroblast growth factor (FGF) pathways, as well as regulation by cilium assembly and the transcription factors encoded by the RUNX2, SIX1, SIX2, SIX4, and TBX1 genes, play critical roles in synchondrosis development. Deletions or activation of these gene products in mice causes the abnormal ossification of cranial synchondrosis and skeletal elements. Gene disruption leads to both similar and markedly different abnormalities in the development of intersphenoid synchondrosis and spheno-occipital synchondrosis, as well as in the phenotypes of synchondroses and skeletal bones. This paper reviews the development of cranial synchondroses, along with its regulation by the signaling pathways and transcription factors, highlighting the differences between intersphenoid synchondrosis and spheno-occipital synchondrosis.

Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines.

Osteosarcoma (OS) is a malignant bone neoplasm, mostly occurring in pediatric patients. OS is characterized by a highly aggressive and metastatically active tumor. Chemotherapy followed by surgical excision is the treatment of choice but is often associated with both chemoresistance and relapse. Hence, it is important to develop further understanding of OS pathogenesis and identify potential therapeutic targets. Both the signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) have been implicated in OS pathogenesis. Crosstalk between mTOR and STAT3 signaling has been shown to regulate hypoxia-induced angiogenesis in other diseases. In this study, we determined using OS cell lines if there is a crosstalk between these two pathways and how that impacts sensitivity to treatment with Rapamycin. OS cell lines exhibited differential sensitivity to mTOR inhibitor Rapamycin. Evaluation of phosphorylated STAT3 showed that in Rapamycin-sensitive 143B cells, the inhibitor decreased phosphorylation of STAT3 at Y705, but not at S727 whereas, in Rapamycin-resistant U2OS cells, the inhibitor decreased S727 phosphorylation but not Y705. However, knockdown of STAT3 in U2OS cells made them sensitive to Rapamycin. Immunofluorescence (IF) analysis showed that mTOR is constitutively activated in the 143B cells but is suppressed in the U2OS cells, indicating that this might be their reason for being resistant to Rapamycin. Both cell lines were sensitive to treatment with the STAT3 inhibitor Napabucasin (NP). Treatment with NP inhibited STAT3 activation at Y705 and additionally inhibited mTOR activation, indicating crosstalk between STAT3 and mTOR signaling pathways. Rapamycin could effectively prevent lung metastasis in an orthotropic OS mice model using 143B cells. However, Rapamycin could not inhibit lung metastasis in mice injected with U2OS cells. The STAT3 inhibitor NP attenuated lung metastasis with the U2OS cells. Our results thus established yet undefined crosstalk of STAT3 and mTOR signaling pathways in OS and highlight the possibility of using mTOR inhibitors for treatment in patients with OS.

Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility.

Toll-like receptor 4 (TLR4) recognizes exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) and initiates the innate immune response. Opioid receptors (μ, δ, and κ) activate inhibitory G-proteins and relieve pain. This review summarizes the following types of TLR4/opioid receptor pathway crosstalk: (a) Opioid receptor agonists non-stereoselectively activate the TLR4 signaling pathway in the central nervous system (CNS), in the absence of lipopolysaccharide (LPS). Opioids bind to TLR4, in a manner parallel to LPS, activating TLR4 signaling, which leads to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression and the production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. (b) Opioid receptor agonists inhibit the LPS-induced TLR4 signaling pathway in peripheral immune cells. Opioids operate as pro-inflammatory cytokines, resulting in neuroinflammation in the CNS, but they mediate immunosuppressive effects in the peripheral immune system. It is apparent that TLR4/opioid receptor pathway crosstalk varies dependent on the cell type and activating stimulus. (c) Both the TLR4 and opioid receptor pathways activate the mitogen-activated protein kinase (MAPK) pathway. This crosstalk is located downstream of the TLR4 and opioid receptor signaling pathways. Furthermore, the classic opioid receptor can also produce pro-inflammatory effects in the CNS via MAPK signaling and induce neuroinflammation. (d) Opioid receptor agonists induce the production of high mobility group box 1 (HMGB1), an endogenous TLR4 agonist, supporting intercellular (neuron-to-glia or glia-to-neuron) interactions. This review also summarizes the potential effects of TLR4/opioid receptor pathway crosstalk on opioid analgesia, immune function, and gastrointestinal motility. Opioids non-stereoselectively activate the TLR4 pathway, and together with the subsequent release of pro-inflammatory cytokines such as IL-1 by glia, this TLR4 signaling initiates the central immune signaling response and modifies opioid pharmacodynamics. The DAMP HMGB1 is associated with the development of neuropathic pain. To explain morphine-induced persistent sensitization, a positive feedback loop has been proposed; this involves an initial morphine-induced amplified release of IL-1β and a subsequent exacerbated release of DAMPs, which increases the activation of TLR4 and the purinergic receptor P2X7R. Opioid receptor (μ, δ, and κ) agonists are involved in many aspects of immunosuppression. The intracellular TLR4/opioid receptor signaling pathway crosstalk induces the formation of the β-arrestin-2/TNF receptor-associated factor 6 (TRAF6) complex, which contributes to morphine-induced inhibition of LPS-induced TNF-α secretion in mast cells. A possible molecular mechanism is that the TLR4 pathway initially triggers the formation of the β-arrestin-2/TRAF6 complex, which is amplified by opioid receptor signaling, suggesting that β-arrestin-2 acts as a functional component of the TLR4 pathway.

Dynamical Regulation of mRNA Distribution by Cross-Talking Signaling Pathways

Gene transcription is a random process in single cells manifested by the observed distribution of mRNA copy numbers in homogeneous cell populations. A central question is to understand how mRNA distribution is modulated under environmental changes. In this work, we initiate a theoretical study on mRNA distribution dynamics for the stochastic transcription model that involves cross-talking signaling pathways to direct gene activation in response to external signals. We first express the distribution in mathematical dynamical formulas under both moderate and high transcriptional upregulations. In each scenario, our further numerical examples display an observed dynamical transition type among three distribution modes for stress genes in yeast. In particular, the intermediate bimodal stage sustains within a certain length of early time and lasts much longer than that generated by the single pathway. This shows the general and robust bimodal transcription regulated by the cross-talk of signaling pathways.

Re: Understanding the Crosstalk of Molecular Factors and Signaling Pathways Reveals Novel Biomarkers of Cisplatin Resistance in Testicular Germ Cell Tumors.

Re: Understanding the Crosstalk of Molecular Factors and Signaling Pathways Reveals Novel Biomarkers of Cisplatin Resistance in Testicular Germ Cell Tumors.

Identification of novel long non-coding RNAs involved in bisphenol A induced immunotoxicity in fish primary macrophages

Bisphenol A (BPA), a well-known environmental endocrine-disrupting chemical (EDC), could pose a great toxicity risk to aquatic organisms. The present study aimed to evaluate the underlying role of long non-coding RNAs (lncRNAs) in BPA-induced immunotoxicity in head kidney (HK) macrophages of the red common carp (Cyprinus carpio), using lncRNA-RNA sequencing (RNA-Seq). In BPA-exposed HK macrophages group, 2,095 and 1,138 differentially expressed mRNAs (DEGs) and lncRNAs (DE-lncRNAs) were obtained, respectively, compared with controls. The qRT-PCR validation results of DEGs and DE-lncRNAs were similar to the RNA-Seq results. The KEGG analysis of DEGs and target genes of DE-lncRNAs have shown that some immune-related signaling pathways, including NF-kappa B, Toll-like receptor, B-cell receptor, Jak-STAT, and Hippo signaling pathways, were severely disrupted by BPA exposure. Moreover, we observed the synergic regulation of some mRNAs involved in immune response such as two hub genes traf6 and mapk1/3 and their upstream lncRNAs in HK macrophages upon the BPA exposure or its analogue bisphenol S (BPS) exposure. This suggested the dysregulation of lncRNAs by BPA or BPS may lead to a change in the expression of hub genes, which affects the cross-talk of various signaling pathways by interaction with other network genes. In conclusion, the present study demonstrates the potential role of lncRNAs in immunotoxicity of bisphenol compounds in red common carp HK macrophages, and our results provide evidence for further exploring lncRNA's role in EDC-induced toxicity in aquatic organisms.

Empowering crop resilience to environmental multiple stress through the modulation of key response components

Crop plants have developed a multitude of defense and adaptation responses to protect themselves against invading pathogens and challenging environmental stresses, mostly operating jointly. The plant perception of overall stress induces a coordinated response mediated by complex signaling networks. Experimental evidences proved that plant response to combined biotic and abiotic stresses substantially diverge from the responses to individual stresses. Moreover, the cross-talk of signaling pathways involved in responding to biotic and abiotic stresses is pivoted on several converging elements able to simultaneously modulate the timing and amplitude of the overall plant response. Comprehensively, the interaction between biotic and abiotic stresses can dramatically changes the plant response to the individual stress and the phenotypical outcome of each stress factor. System biology and data mining can synergistically help biologists in finding out regulative mechanisms and key genes controlling the response to biotic and abiotic stresses. Deploying new genetic engineering solutions can rely on the modification of genes involved in resistance/tolerance processes and/or in the modulation of regulatory elements. Finally, a model of the engineered crop for enhanced tolerance to pressures resulting from invasive pathogens and abiotic constraints in semiarid and warm environment is discussed.