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Lojk, Jasna, and Janja Marc. "Roles of Non-Canonical Wnt Signalling Pathways in Bone Biology." International Journal of Molecular Sciences 22, no. 19 (October 7, 2021): 10840. http://dx.doi.org/10.3390/ijms221910840.
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The Wnt signalling pathway is one of the central signalling pathways in bone development, homeostasis and regulation of bone mineral density. It consists of numerous Wnt ligands, receptors and co-receptors, which ensure tight spatiotemporal regulation of Wnt signalling pathway activity and thus tight regulation of bone tissue homeostasis. This enables maintenance of optimal mineral density, tissue healing and adaptation to changes in bone loading. While the role of the canonical/β-catenin Wnt signalling pathway in bone homeostasis is relatively well researched, Wnt ligands can also activate several non-canonical, β-catenin independent signalling pathways with important effects on bone tissue. In this review, we will provide a thorough overview of the current knowledge on different non-canonical Wnt signalling pathways involved in bone biology, focusing especially on the pathways that affect bone cell differentiation, maturation and function, processes involved in bone tissue structure regulation. We will describe the role of the two most known non-canonical pathways (Wnt/planar cell polarity pathways and Wnt/Ca2+ pathway), as well as other signalling pathways with a strong role in bone biology that communicate with the Wnt signalling pathway through non-canonical Wnt signalling. Our goal is to bring additional attention to these still not well researched but important pathways in the regulation of bone biology in the hope of prompting additional research in the area of non-canonical Wnt signalling pathways.
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Sanz-Ezquerro, Juan José, and Ana Cuenda. "p38 Signalling Pathway." International Journal of Molecular Sciences 22, no. 3 (January 20, 2021): 1003. http://dx.doi.org/10.3390/ijms22031003.
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p38 Mitogen activated protein kinases (p38MAPK) are a highly evolutionary conserved group of protein kinases, which are central for cell adaptation to environmental changes as well as for immune response, inflammation, tissue regeneration, and tumour formation [...]
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Gomi, Kenji, and Makoto Matsuoka. "Gibberellin signalling pathway." Current Opinion in Plant Biology 6, no. 5 (October 2003): 489–93. http://dx.doi.org/10.1016/s1369-5266(03)00079-7.
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Wang, Lin-Qing, Jing-Cai Liu, Chun-Lei Chen, Shun-Feng Cheng, Xiao-Feng Sun, Yong Zhao, Shen Yin, et al. "Regulation of primordial follicle recruitment by cross-talk between the Notch and phosphatase and tensin homologue (PTEN)/AKT pathways." Reproduction, Fertility and Development 28, no. 6 (2016): 700. http://dx.doi.org/10.1071/rd14212.
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The growth of oocytes and the development of follicles require certain pathways involved in cell proliferation and survival, such as the phosphatidylinositol 3-kinase (PI3K) pathway and the Notch signalling pathway. The aim of the present study was to investigate the interaction between Notch and the PI3K/AKT signalling pathways and their effects on primordial follicle recruitment. When the Notch pathway was inhibited by L-685,458 or N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester (DAPT) in vitro, the expression of genes in the pathway and the percentage of oocytes in growing follicles decreased significantly in mouse ovaries. By 2 days postpartum, ovaries exposed to DAPT, short interference (si) RNA against Notch1 or siRNA against Hairy and enhancer of split-1 (Hes1) had significantly decreased expression of HES1, the target protein of the Notch signalling pathway. In contrast, expression of phosphatase and tensin homologue (Pten), a negative regulator of the AKT signalling pathway, was increased significantly. Co immunoprecipitation (Co-IP) revealed an interaction between HES1 and PTEN. In addition, inhibition of the Notch signalling pathway suppressed AKT phosphorylation and the proliferation of granulosa cells. In conclusion, the recruitment of primordial follicles was affected by the proliferation of granulosa cells and regulation of the interaction between the Notch and PI3K/AKT signalling pathways.
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Jarnæss, E., and K. Taskén. "Spatiotemporal control of cAMP signalling processes by anchored signalling complexes." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 931–37. http://dx.doi.org/10.1042/bst0350931.
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Ligand-induced changes in cAMP concentration vary in duration, amplitude and extension into the cell. cAMP microdomains are shaped by adenylate cyclases that form cAMP as well as PDEs (phosphodiesterases) that degrade cAMP. Various extracellular signals converge on the cAMP/PKA (protein kinase A) pathway through ligand binding to GPCRs (G-protein-coupled receptors) and the cAMP/PKA pathway is therefore tightly regulated on several levels to maintain specificity in the multitude of signal inputs. AKAPs (A-kinase-anchoring proteins) target PKA to specific substrates and distinct subcellular compartments, providing spatial and temporal specificity for mediation of biological effects channelled through the cAMP/PKA pathway. AKAPs also serve as scaffolding proteins that assemble PKA together with signal terminators such as phosphoprotein phosphatases and cAMP-specific PDEs as well as components of other signalling pathways into multiprotein signalling complexes.
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Ma, Chen-Yu, Yu-Qian Ma, and Min Deng. "Mechanism of Zhen Wu Decoction in the Treatment of Heart Failure Based on Network Pharmacology and Molecular Docking." Evidence-Based Complementary and Alternative Medicine 2022 (March 15, 2022): 1–10. http://dx.doi.org/10.1155/2022/4877920.
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Heart failure (HF) is a serious manifestation or advanced stage of various cardiovascular diseases, and its mortality and rehospitalization rate are still on the rise in China. Based on the network pharmacology method, 59 components of Zhen Wu decoction (ZWD) and 83 target genes related to HF were obtained. Through the PPI network, four potential therapeutic targets were identified: AKT1, IL6, JUN, and MAPK8. The beneficial components of ZWD might intervene HF through the AGE-RAGE signalling pathway in the diabetes component, fluid shear stress and atherosclerosis, the TNF signalling pathway, TB, and Kaposi sarcoma related herpesvirus infection, according to a KEGG enrichment study. The protein interaction network of candidate targets was constructed by the STRING database, and the protein interaction network was clustered by MEODE software. GO and KEGG enrichment analyses were performed on the core modules obtained by clustering. Finally, AutoDock Vina software was used for molecular docking verification of key targets and active ingredients. The result was that 75 active ingredients and 109 genes were screened as potential active ingredients and potential targets of Shengjie Tongyu decoction for CHF treatment. The main active components were quercetin, luteolin, kaempferol, dehydrated icariin, isorhamnetin, formononetin, and other flavonoids. Il-6, MAPK1, MAPK8, AKT1, VEGFA, and JUN were selected as the core targets. Molecular docking showed that the key components were well connected with the target. GO enrichment analysis showed that Shengjie Tongyu decoction could play a role through multiple biological pathways including angiogenesis, regulation of endothelial cell proliferation, binding of cytokine receptors, negative regulation of apoptotic signalling pathways, regulation of nitric oxide synthase activity, and reactive oxygen metabolism. Key pathways mainly focus on the toll-like receptor signalling pathway, nod-like receptor signalling pathway, MAPK signalling pathway, mTOR signalling pathway, JAK-STAT signalling pathway, VEGF signalling pathway, and other pathways. Through molecular docking technology, it was found that a variety of effective components in ZWD, such as kaempferol. Molecular docking technology has preliminatively verified the network pharmacology and laid a foundation for the follow-up pharmacological research.
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Hülsken, Jörg, and Jürgen Behrens. "The Wnt signalling pathway." Journal of Cell Science 113, no. 20 (January 1, 2000): 3545. http://dx.doi.org/10.1242/jcs.113.20.3545.
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Huelsken, J. "The Wnt signalling pathway." Journal of Cell Science 115, no. 21 (November 1, 2002): 3977–78. http://dx.doi.org/10.1242/jcs.00089.
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CARTER-SU, CHRISTIN, ANTHONY PJ KING, LAWRENCE S. ARGETSINGER, LISA S. SMIT, JOYCE VANDERKUUR, and GEORGE S. CAMPBELL. "Signalling Pathway of GH." Endocrine Journal 43, Suppl (1996): S65—S70. http://dx.doi.org/10.1507/endocrj.43.suppl_s65.
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Lizcano, Jose M., and Dario R. Alessi. "The insulin signalling pathway." Current Biology 12, no. 7 (April 2002): R236—R238. http://dx.doi.org/10.1016/s0960-9822(02)00777-7.
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Rydenfelt, Mattias, Bertram Klinger, Martina Klünemann, and Nils Blüthgen. "SPEED2: inferring upstream pathway activity from differential gene expression." Nucleic Acids Research 48, W1 (April 20, 2020): W307—W312. http://dx.doi.org/10.1093/nar/gkaa236.
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Abstract Extracting signalling pathway activities from transcriptome data is important to infer mechanistic origins of transcriptomic dysregulation, for example in disease. A popular method to do so is by enrichment analysis of signature genes in e.g. differentially regulated genes. Previously, we derived signatures for signalling pathways by integrating public perturbation transcriptome data and generated a signature database called SPEED (Signalling Pathway Enrichment using Experimental Datasets), for which we here present a substantial upgrade as SPEED2. This web server hosts consensus signatures for 16 signalling pathways that are derived from a large number of transcriptomic signalling perturbation experiments. When providing a gene list of e.g. differentially expressed genes, the web server allows to infer signalling pathways that likely caused these genes to be deregulated. In addition to signature lists, we derive ‘continuous’ gene signatures, in a transparent and automated fashion without any fine-tuning, and describe a new algorithm to score these signatures.
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Langiu, Monica, Philipp Bechstein, Sonja Neumann, Gabriele Spohn, and Erik Maronde. "Regulation of CRE-Dependent Transcriptional Activity in a Mouse Suprachiasmatic Nucleus Cell Line." International Journal of Molecular Sciences 23, no. 20 (October 13, 2022): 12226. http://dx.doi.org/10.3390/ijms232012226.
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We evaluated the signalling framework of immortalized cells from the hypothalamic suprachiasmatic nucleus (SCN) of the mouse. We selected a vasoactive intestinal peptide (VIP)-positive sub-clone of immortalized mouse SCN-cells stably expressing a cAMP-regulated-element (CRE)-luciferase construct named SCNCRE. We characterized these cells in terms of their status as neuronal cells, as well as for important components of the cAMP-dependent signal transduction pathway and compared them to SCN ex vivo. SCNCRE cells were treated with agents that modulate different intracellular signalling pathways to investigate their potency and timing for transcriptional CRE-dependent signalling. Several activating pathways modulate SCN neuronal signalling via the cAMP-regulated-element (CRE: TGACGCTA) and phosphorylation of transcription factors such as cAMP-regulated-element-binding protein (CREB). CRE-luciferase activity induced by different cAMP-signalling pathway-modulating agents displayed a variety of substance-specific dose and time-dependent profiles and interactions relevant to the regulation of SCN physiology. Moreover, the induction of the protein kinase C (PKC) pathway by phorbol ester application modulates the CRE-dependent signalling pathway as well. In conclusion, the cAMP/PKA- and the PKC-regulated pathways individually and in combination modulate the final CRE-dependent transcriptional output.
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Joshipura, Akshat, and Salmataj S. A. Salmataj S A. "diopathic Pulmonary Fibrosis: A Review on Molecular and Cellular Mechanisms." Biomedical and Pharmacology Journal 15, no. 1 (March 31, 2022): 291–97. http://dx.doi.org/10.13005/bpj/2366.
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Idiopathic pulmonary fibrosis is a progressive disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is attracting considerable attention due to disease acceleration and substantial mortality. The biomechanical properties of tissues are sensed and responded to by mechanotransduction pathways that facilitate sensing of changes in mechanical cues by tissue resident cells and convert the mechanical signals into downstream biochemical signals. In this review pathways such as Wnt/β-catenin pathway, TGF-β/Smad signaling pathway and EMT in IPF, VEGF and its relation with PI3K–Akt signalling pathway, PI3-Akt pathway, PDGF Signalling Pathway, Hippo/YAP signalling, JAK/STAT pathway, Rnd3/p190/Rho-Gap pathway have been discussed. This review also covers current therapeutic strategies in relation to idiopathic pulmonary fibrosis.
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Agostino, Mark, and Sebastian Öther-Gee Pohl. "The structural biology of canonical Wnt signalling." Biochemical Society Transactions 48, no. 4 (July 29, 2020): 1765–80. http://dx.doi.org/10.1042/bst20200243.
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The Wnt signalling pathways are of great importance in embryonic development and oncogenesis. Canonical and non-canonical Wnt signalling pathways are known, with the canonical (or β-catenin dependent) pathway being perhaps the best studied of these. While structural knowledge of proteins and interactions involved in canonical Wnt signalling has accumulated over the past 20 years, the pace of discovery has increased in recent years, with the structures of several key proteins and assemblies in the pathway being released. In this review, we provide a brief overview of canonical Wnt signalling, followed by a comprehensive overview of currently available X-ray, NMR and cryoEM data elaborating the structures of proteins and interactions involved in canonical Wnt signalling. While the volume of structures available is considerable, numerous gaps in knowledge remain, particularly a comprehensive understanding of the assembly of large multiprotein complexes mediating key aspects of pathway, as well as understanding the structure and activation of membrane receptors in the pathway. Nonetheless, the presently available data affords considerable opportunities for structure-based drug design efforts targeting canonical Wnt signalling.
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Babonis, Leslie S., and Mark Q. Martindale. "Phylogenetic evidence for the modular evolution of metazoan signalling pathways." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1713 (February 5, 2017): 20150477. http://dx.doi.org/10.1098/rstb.2015.0477.
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Communication among cells was paramount to the evolutionary increase in cell type diversity and, ultimately, the origin of large body size. Across the diversity of Metazoa, there are only few conserved cell signalling pathways known to orchestrate the complex cell and tissue interactions regulating development; thus, modification to these few pathways has been responsible for generating diversity during the evolution of animals. Here, we summarize evidence for the origin and putative function of the intracellular, membrane-bound and secreted components of seven metazoan cell signalling pathways with a special focus on early branching metazoans (ctenophores, poriferans, placozoans and cnidarians) and basal unikonts (amoebozoans, fungi, filastereans and choanoflagellates). We highlight the modular incorporation of intra- and extracellular components in each signalling pathway and suggest that increases in the complexity of the extracellular matrix may have further promoted the modulation of cell signalling during metazoan evolution. Most importantly, this updated view of metazoan signalling pathways highlights the need for explicit study of canonical signalling pathway components in taxa that do not operate a complete signalling pathway. Studies like these are critical for developing a deeper understanding of the evolution of cell signalling. This article is part of the themed issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’.
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Chen, Xiao-Wu, Yuan Ming Di, Jian Zhang, Zhi-Wei Zhou, Chun Guang Li, and Shu-Feng Zhou. "Interaction of Herbal Compounds with Biological Targets: A Case Study with Berberine." Scientific World Journal 2012 (2012): 1–31. http://dx.doi.org/10.1100/2012/708292.
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Berberine is one of the main alkaloids found in the Chinese herb Huang lian (Rhizoma Coptidis), which has been reported to have multiple pharmacological activities. This study aimed to analyze the molecular targets of berberine based on literature data followed by a pathway analysis using the PANTHER program. PANTHER analysis of berberine targets showed that the most classes of molecular functions include receptor binding, kinase activity, protein binding, transcription activity, DNA binding, and kinase regulator activity. Based on the biological process classification ofin vitroberberine targets, those targets related to signal transduction, intracellular signalling cascade, cell surface receptor-linked signal transduction, cell motion, cell cycle control, immunity system process, and protein metabolic process are most frequently involved. In addition, berberine was found to interact with a mixture of biological pathways, such as Alzheimer’s disease-presenilin and -secretase pathways, angiogenesis, apoptosis signalling pathway, FAS signalling pathway, Hungtington disease, inflammation mediated by chemokine and cytokine signalling pathways, interleukin signalling pathway, and p53 pathways. We also explored the possible mechanism of action for the anti-diabetic effect of berberine. Further studies are warranted to elucidate the mechanisms of action of berberine using systems biology approach.
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Oceandy, Delvac, Bella Amanda, Faisal Ashari, Zakiyatul Faizah, M. Aziz, and Nicholas Stafford. "The Cross-Talk Between the TNF-α and RASSF-Hippo Signalling Pathways." International Journal of Molecular Sciences 20, no. 9 (May 11, 2019): 2346. http://dx.doi.org/10.3390/ijms20092346.
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The regulation of cell death through apoptosis is essential to a number of physiological processes. Defective apoptosis regulation is associated with many abnormalities including anomalies in organ development, altered immune response and the development of cancer. Several signalling pathways are known to regulate apoptosis including the Tumour Necrosis Factor-α (TNF-α) and Hippo signalling pathways. In this paper we review the cross-talk between the TNF-α pathway and the Hippo signalling pathway. Several molecules that tightly regulate the Hippo pathway, such as members of the Ras-association domain family member (RASSF) family proteins, interact and modulate some key proteins within the TNF-α pathway. Meanwhile, TNF-α stimulation also affects the expression and activation of core components of the Hippo pathway. This implies the crucial role of signal integration between these two major pathways in regulating apoptosis.
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MATHIAS, Shalini, Louis A. PEÑA, and Richard N. KOLESNICK. "Signal transduction of stress via ceramide." Biochemical Journal 335, no. 3 (November 1, 1998): 465–80. http://dx.doi.org/10.1042/bj3350465.
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The sphingomyelin (SM) pathway is a ubiquitous, evolutionarily conserved signalling system analogous to conventional systems such as the cAMP and phosphoinositide pathways. Ceramide, which serves as second messenger in this pathway, is generated from SM by the action of a neutral or acidic SMase, or by de novosynthesis co-ordinated through the enzyme ceramide synthase. A number of direct targets for ceramide action have now been identified, including ceramide-activated protein kinase, ceramide-activated protein phosphatase and protein kinase Cζ, which couple the SM pathway to well defined intracellular signalling cascades. The SM pathway induces differentiation, proliferation or growth arrest, depending on the cell type. Very often, however, the outcome of signalling through this pathway is apoptosis. Mammalian systems respond to diverse stresses with ceramide generation, and recent studies show that yeast manifest a form of this response. Thus ceramide signalling is an older stress response system than the caspase/apoptotic death pathway, and hence these two pathways must have become linked later in evolution. Signalling of the stress response through ceramide appears to play a role in the development of human diseases, including ischaemia/reperfusion injury, insulin resistance and diabetes, atherogenesis, septic shock and ovarian failure. Further, ceramide signalling mediates the therapeutic effects of chemotherapy and radiation in some cells. An understanding of the mechanisms by which ceramide regulates physiological and pathological events in specific cells may provide new targets for pharmacological intervention.
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Gorvin, Caroline M. "Insights into calcium-sensing receptor trafficking and biased signalling by studies of calcium homeostasis." Journal of Molecular Endocrinology 61, no. 1 (July 2018): R1—R12. http://dx.doi.org/10.1530/jme-18-0049.
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The calcium-sensing receptor (CASR) is a class C G-protein-coupled receptor (GPCR) that detects extracellular calcium concentrations, and modulates parathyroid hormone secretion and urinary calcium excretion to maintain calcium homeostasis. The CASR utilises multiple heterotrimeric G-proteins to mediate signalling effects including activation of intracellular calcium release; mitogen-activated protein kinase (MAPK) pathways; membrane ruffling; and inhibition of cAMP production. By studying germline mutations in the CASR and proteins within its signalling pathway that cause hyper- and hypocalcaemic disorders, novel mechanisms governing GPCR signalling and trafficking have been elucidated. This review focusses on two recently described pathways that provide novel insights into CASR signalling and trafficking mechanisms. The first, identified by studying a CASR gain-of-function mutation that causes autosomal dominant hypocalcaemia (ADH), demonstrated a structural motif located between the third transmembrane domain and the second extracellular loop of the CASR that mediates biased signalling by activating a novel β-arrestin-mediated G-protein-independent pathway. The second, in which the mechanism by which adaptor protein-2 σ-subunit (AP2σ) mutations cause familial hypocalciuric hypercalcaemia (FHH) was investigated, demonstrated that AP2σ mutations impair CASR internalisation and reduce multiple CASR-mediated signalling pathways. Furthermore, these studies showed that the CASR can signal from the cell surface using multiple G-protein pathways, whilst sustained signalling is mediated only by the Gq/11 pathway. Thus, studies of FHH- and ADH-associated mutations have revealed novel steps by which CASR mediates signalling and compartmental bias, and these pathways could provide new targets for therapies for patients with calcaemic disorders.
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Sharma, Varun Kumar, Charu Tyagi, Yugandhar P. Reddy, Jayanand Manjhi, and Lomas Kumar Tomar. "Transforming growth factor beta signaling in hepatocellular carcinoma: as a victim or culprit?" International Journal of Advances in Medicine 6, no. 3 (May 24, 2019): 991. http://dx.doi.org/10.18203/2349-3933.ijam20192279.
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The transforming growth factor-β (TGFβ) signalling pathway control various cellular function and play a pivotal role in tumour suppression. In contrary, overexpression of TGFβ is linked to promote the cancer development. TGFβ facilitate cell-growth and cell-differentiation process which support tumour propagation. In case of hepatocellular carcinoma (HCC), TGFβ signalling pathway is the master regulator of HCCs pathogenesis and functionally involved in the regulation of HCCs phenotype via modulating the downstream signalling pathways. In this article, we have highlighted the contradictory behaviour of TGFβ in hepatocellular carcinoma. Observations suggest that the TGFβ signalling pathway is positively correlated to the expression of genes linked with various hepatic pathological conditions, including fibrosis, cirrhosis, inflammation and cancer. TGFβ pathway play dual role as pro and anti-tumoural activities in cancer cells depending on their context.
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Quinn, Niall P., Lucía García-Gutiérrez, Carolanne Doherty, Alexander von Kriegsheim, Emma Fallahi, David B. Sacks, and David Matallanas. "IQGAP1 Is a Scaffold of the Core Proteins of the Hippo Pathway and Negatively Regulates the Pro-Apoptotic Signal Mediated by This Pathway." Cells 10, no. 2 (February 23, 2021): 478. http://dx.doi.org/10.3390/cells10020478.
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The Hippo pathway regulates a complex signalling network which mediates several biological functions including cell proliferation, organ size and apoptosis. Several scaffold proteins regulate the crosstalk of the members of the pathway with other signalling pathways and play an important role in the diverse output controlled by this pathway. In this study we have identified the scaffold protein IQGAP1 as a novel interactor of the core kinases of the Hippo pathway, MST2 and LATS1. Our results indicate that IQGAP1 scaffolds MST2 and LATS1 supresses their kinase activity and YAP1-dependent transcription. Additionally, we show that IQGAP1 is a negative regulator of the non-canonical pro-apoptotic pathway and may enable the crosstalk between this pathway and the ERK and AKT signalling modules. Our data also show that bile acids regulate the IQGAP1-MST2-LATS1 signalling module in hepatocellular carcinoma cells, which could be necessary for the inhibition of MST2-dependent apoptosis and hepatocyte transformation.
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Barbolina, Maria V., Rebecca J. Burkhalter, and M. Sharon Stack. "Diverse mechanisms for activation of Wnt signalling in the ovarian tumour microenvironment." Biochemical Journal 437, no. 1 (June 14, 2011): 1–12. http://dx.doi.org/10.1042/bj20110112.
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Wnt signalling pathways have been shown to play key roles in both normal development and tumorigenesis. Progression of many human cancers is associated with defined mutations in Wnt pathway components that result in dysregulated β-catenin-mediated gene transcription. Although Wnt pathway mutations are rare in epithelial ovarian cancer (with the exception of the endometrioid histotype), accumulating evidence supports a role for Wnt signalling in ovarian tumorigenesis in the absence of genetic mutations. The present review summarizes evidence in support of activated Wnt signalling in ovarian tumours and discusses alternative mechanisms for Wnt pathway activation in the ovarian tumour microenvironment.
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Pfeifer, Andrea C., Jens Timmer, and Ursula Klingmüller. "Systems biology of JAK/STAT signalling." Essays in Biochemistry 45 (September 30, 2008): 109–20. http://dx.doi.org/10.1042/bse0450109.
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Signalling in multicellular organisms is mediated by complex networks that integrate extracellular and intracellular signals to generate appropriate responses regulating cell proliferation, differentiation and survival. Downstream of many cytokine and growth hormone receptors, receptor-associated JAKs (Janus kinases) activate transcription factors of the STAT (signal transducer and activator of transcription) protein family and thereby mediate signal transduction from the plasma membrane to the nucleus. The JAK/STAT pathway has been shown to be constitutively activated in a wide array of human malignancies. To elucidate mechanisms contributing to tumour formation and identify system properties of the JAK/STAT signalling pathway, a systems biology approach can be employed. So far the majority of studies available have focused on down-regulation of the signalling pathway based on simulations. However, a data-based model of the core module of the JAK2/STAT5 signalling pathway showed that rapid nucleocytoplasmic cycling of STAT5 is an essential pathway property. In the future, combining assays for quantitative analysis at different levels will be important to gain deeper insight into molecular mechanisms regulating intracellular communication mediated by such complex dynamic systems as signalling pathways and their targets.
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Comoglio, Paolo M. "Pathway specificity for Met signalling." Nature Cell Biology 3, no. 7 (July 2001): E161—E162. http://dx.doi.org/10.1038/35083116.
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Arias, Alfonso Martinez, Anthony MC Browntand, and Keith Brennan. "Wnt signalling: pathway or network?" Current Opinion in Genetics & Development 9, no. 4 (August 1999): 447–54. http://dx.doi.org/10.1016/s0959-437x(99)80068-9.
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Johnston, S. "Targeting ER and signalling pathway." European Journal of Cancer Supplements 6, no. 7 (April 2008): 164. http://dx.doi.org/10.1016/s1359-6349(08)70694-3.
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Parsons, D. Williams, Tian-Li Wang, Yardena Samuels, Alberto Bardelli, Jordan M. Cummins, Laura DeLong, Natalie Silliman, et al. "Mutations in a signalling pathway." Nature 436, no. 7052 (August 2005): 792. http://dx.doi.org/10.1038/436792a.
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Landström, Marene. "The TAK1–TRAF6 signalling pathway." International Journal of Biochemistry & Cell Biology 42, no. 5 (May 2010): 585–89. http://dx.doi.org/10.1016/j.biocel.2009.12.023.
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Wang, Mingyang, Weiwei Wu, Lin Li, Jianbin He, Sheng Huang, Si Chen, Jia Chen, Miao Long, Shuhua Yang, and Peng Li. "Analysis of the miRNA Expression Profiles in the Zearalenone-Exposed TM3 Leydig Cell Line." International Journal of Molecular Sciences 20, no. 3 (February 1, 2019): 635. http://dx.doi.org/10.3390/ijms20030635.
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Zearalenone (ZEN), an important environmental pollutant, can cause serious harm to human and animal health. The aim of our study was to examine the effect of zearalenone (ZEN) on miRNA expression profiles in the mouse Leydig cell line (TM3 Leydig cell line) by miRNA sequencing. The effect of ZEN on the viability of TM3 Leydig cells was verified by Cell Counting Kit-8 (CCK-8). MiRNA sequencing was performed 24 h after the exposure of TM3 Leydig cells with 50 μmol/L of ZEN. Bioinformatics predicted the miRNA target genes, performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and conducted miRNA-gene-pathway mapping to show the relationship between miRNA, the target gene, and the signalling pathway. The expression levels of miRNA and the miRNA target genes associated with ZEN toxicology were verified by quantitative real-time polymerase chain reaction. The miRNA sequencing revealed a significant change (p < 0.05) in the 197 miRNAs in the ZEN-treated and control groups, among which 86 were up-regulated and 111 were down-regulated. GO analysis of the target genes of these miRNAs indicated various biological functions. KEGG analysis showed that the predicted miRNA target genes were involved in signalling pathways, such as cancer, apoptosis, and oxidation, namely, the Ras signalling pathway, Rap1 signalling pathway, PI3K-AKT signalling pathway, Foxo signalling pathway, and AMPK signalling pathway. These results suggest that ZEN, as an estrogen-like toxin, is regulated by microRNAs. Our results can help to examine the toxicological effects of ZEN-regulated miRNAs on germ cells.
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Romano, David, David Matallanas, Dennie T. Frederick, Keith T. Flaherty, and Walter Kolch. "One Hippo and many masters: differential regulation of the Hippo pathway in cancer." Biochemical Society Transactions 42, no. 4 (August 1, 2014): 816–21. http://dx.doi.org/10.1042/bst20140030.
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The Hippo/MST2 (mammalian sterile 20-like kinase 2) pathway is a signalling cascade evolutionarily conserved in its structure. Originally described in Drosophila melanogaster as a regulator of organ size, this pathway has greater functions in mammals. Disturbance of mammalian MST2 pathway is associated with tumorigenesis by affecting apoptosis, cell cycle and polarity. In addition, this pathway has been shown to cross-talk with mitogenic pathways at multiple levels. In the present mini-review, we discuss our contribution highlighting the regulation of MST2 signalling by frequently observed oncogenic perturbations affecting mitogenic pathways. In particular, we review the role of RAS isoforms and PI3K (phosphoinositide 3-kinase)/Akt in the regulation of MST2 activity by phosphorylation. We also put the emphasis on RAF-induced control of MST2 signalling by protein–protein interactions. Finally, we recapitulate some of the direct mechanisms, such as ubiquitin-dependent degradation or gene silencing by promoter hypermethylation, involved in MST2 pathway component down-regulation in cancers.
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Pan, Qiaowei, Tomas Kay, Alexandra Depincé, Mateus Adolfi, Manfred Schartl, Yann Guiguen, and Amaury Herpin. "Evolution of master sex determiners: TGF-β signalling pathways at regulatory crossroads." Philosophical Transactions of the Royal Society B: Biological Sciences 376, no. 1832 (July 12, 2021): 20200091. http://dx.doi.org/10.1098/rstb.2020.0091.
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To date, more than 20 different vertebrate master sex-determining genes have been identified on different sex chromosomes of mammals, birds, frogs and fish. Interestingly, six of these genes are transcription factors ( Dmrt1 - or Sox3 - related) and 13 others belong to the TGF-β signalling pathway ( Amh , Amhr2 , Bmpr1b , Gsdf and Gdf6 ). This pattern suggests that only a limited group of factors/signalling pathways are prone to become top regulators again and again. Although being clearly a subordinate member of the sex-regulatory network in mammals, the TGF-β signalling pathway made it to the top recurrently and independently. Facing this rolling wave of TGF-β signalling pathways, this review will decipher how the TGF-β signalling pathways cope with the canonical sex gene regulatory network and challenge the current evolutionary concepts accounting for the diversity of sex-determining mechanisms. This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
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Cunningham, Richard, and Carsten Gram Hansen. "The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer." Clinical Science 136, no. 3 (February 2022): 197–222. http://dx.doi.org/10.1042/cs20201474.
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Abstract Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over the last decade is the Hippo signalling pathway. Consisting of two antagonistic modules, the pathway plays an integral role in both tumour suppressive and oncogenic processes, generally via regulation of a diverse set of genes involved in a range of biological functions. This review discusses the history of the pathway within the context of cancer and explores some of the most recent discoveries as to how this critical transducer of cellular signalling can influence cancer progression. A special focus is on the various recent efforts to therapeutically target the key effectors of the pathway in both preclinical and clinical settings.
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Kofahl, Bente, and Jana Wolf. "Mathematical modelling of Wnt/β-catenin signalling." Biochemical Society Transactions 38, no. 5 (September 24, 2010): 1281–85. http://dx.doi.org/10.1042/bst0381281.
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The Wnt/β-catenin pathway plays an important role in development and disease. Theoretical approaches have been used to describe this pathway and have provided intriguing insights into its signalling characteristics. In the present paper, we review mathematical models of the pathway. We focus on a quantitative kinetic model for canonical Wnt/β-catenin signalling describing the reactions of the pathway's core compounds [Lee, Salic, Krüger, Heinrich and Kirschner (2003) PLoS Biol. 1, 116–132]. Numerous modifications and further analyses with respect to signalling characteristics, transcriptional feedback and cross-talk were performed. In addition, the role of β-catenin in gene expression and cell–cell adhesion as well as spatial aspects of signalling are investigated in various theoretical models.
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Zen, Ayman Al Haj, and Paolo Madeddu. "Notch signalling in ischaemia-induced angiogenesis." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1221–27. http://dx.doi.org/10.1042/bst0371221.
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Notch signalling represents a key pathway essential for normal vascular development. Recently, great attention has been focused on the implication of Notch pathway components in postnatal angiogenesis and regenerative medicine. This paper critically reviews the most recent findings supporting the role of Notch in ischaemia-induced neovascularization. Notch signalling reportedly regulates several steps of the reparative process occurring in ischaemic tissues, including sprouting angiogenesis, vessel maturation, interaction of vascular cells with recruited leucocytes and skeletal myocyte regeneration. Further characterization of Notch interaction with other signalling pathways might help identify novel targets for therapeutic angiogenesis.
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Henshall, D. C. "Apoptosis signalling pathways in seizure-induced neuronal death and epilepsy." Biochemical Society Transactions 35, no. 2 (March 20, 2007): 421–23. http://dx.doi.org/10.1042/bst0350421.
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Delineating the molecular pathways underlying seizure-induced neuronal death may yield novel strategies for brain protection against prolonged or repetitive seizures. Glutamate-mediated excitotoxicity and necrosis is a primary contributing mechanism but seizures also activate programmed (apoptotic) cell death pathways. Apoptosis signalling pathways are typically initiated following perturbation of intracellular organelle function (intrinsic pathway) or by activated cell-surface-expressed death receptors (extrinsic pathway), with signalling cascades orchestrated in part by the Bcl-2 and caspase gene families. In this review, evidence for these pathways from experimental seizure modelling and clinical material from patients with intractable temporal lobe epilepsy is examined. Seizures cause mitochondrial dysfunction and activate intrinsic pathway components including pro-apoptotic Bcl-2 family proteins and caspases, processes that may be partly calcium-induced. The ER (endoplasmic reticulum) has emerged as a major intrinsic pathway trigger for apoptosis and its function may also be compromised following seizures and in epilepsy. The extrinsic, death-receptor-dependent pathway is also rapidly engaged following experimental seizures and in patient brain, supporting a previously unexpected apical role for a calcium-independent pathway. When considered alongside emerging functions of apoptosis-regulatory proteins in non-cell-death processes, including regulating intracellular calcium release and neuronal (re)structuring, apoptosis signalling pathways can be viewed as an important developing focus of research into how to obviate the deleterious impact of seizures on the brain.
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Whitmarsh, A. J. "The JIP family of MAPK scaffold proteins." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 828–32. http://dx.doi.org/10.1042/bst0340828.
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The components of MAPK (mitogen-activated protein kinase) signalling pathways can assemble into complexes that are co-ordinated by regulatory proteins including scaffold proteins. There is increasing evidence that scaffold proteins (i) maintain signalling specificity and facilitate the activation of pathway components, (ii) localize pathway components to particular subcellular sites or to specific targets, and (iii) serve as a point of signal integration to allow regulation of MAPK pathways by other signalling events in the cell. One family of scaffold proteins that regulate signalling by stress-activated MAPKs are the JIPs [JNK (c-Jun N-terminal kinase)-interacting proteins]. JIP proteins have been demonstrated to form complexes with specific JNK and p38 MAPK signalling modules and to play important roles in brain development, neuronal trafficking, apoptosis, β-cell function and insulin responses. Here, I briefly review our current understanding of the biochemical properties and physiological roles of JIP proteins.
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Liu, Keying. "Immune, metabolism and therapeutic targets in RA (Rheumatoid Arthritis)." BIO Web of Conferences 55 (2022): 01016. http://dx.doi.org/10.1051/bioconf/20225501016.
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Rheumatoid arthritis is a classic autoimmune disease, the pathogenesis of which is closely linked to the auto-reactivity of immune cells and joint inflammation. Three cell types, namely T cells, macrophages and fibroblast-like synoviocytes (FLS), play an important role in the pathogenesis of RA. Numerous studies have pointed to a metabolic reprogramming of T cells, macrophages and FLS in the pathogenesis of RA arthritis, with alterations in different metabolic pathways of cells, mainly producing a shift from oxidative phosphorylation (OXPHOS) to glycolysis, in addition to lipid metabolism and amino acid metabolism which are also altered in the cellular activation state. Metabolic changes are regulated by metabolism-related signalling pathways, and RA is associated with two representative signalling pathways, namely the mTOR signalling pathway and the AMPK signalling pathway. In RA, both signalling pathways are activated or inhibited, and through a series of cascade reactions, different gene expressions are ultimately induced, altering intracellular metabolic pathways and promoting pro-inflammatory functions (e.g. pro-inflammatory cytokine release and FLS phenotypes), or inhibiting the expression of genes related to immune tolerance. Targeting key components of metabolic signalling pathways and key enzymes in cellular metabolic pathways in RA has emerged as a new way of finding drugs for RA, and many modulators targeting these targets have been extensively studied for their therapeutic effects in RA. In this article, we focus on cellular metabolic alterations in RA, related signalling pathways and possible drugs targeting RA metabolic pathways.
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Fu, Yang, Shanshan Sun, Xiaojun Man, and Chuize Kong. "Increased expression of RUNX1 in clear cell renal cell carcinoma predicts poor prognosis." PeerJ 7 (October 2, 2019): e7854. http://dx.doi.org/10.7717/peerj.7854.
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Background Runt-related transcription factor 1 (RUNX1) was previously reported to play a dual role in promoting or suppressing tumorigenesis in various malignancies. A public dataset from The Cancer Genome Atlas (TCGA) was used to evaluate the role of RUNX1 in clear cell renal cell carcinoma (ccRCC). Methods The Wilcoxon signed-rank test was used to compare the expression of RUNX1 in ccRCC tissues and normal tissues. The Wilcoxon signed-rank test and logistic regression were utilized to investigate the relationship between clinicopathological factors and RUNX1 expression. Additionally, we analysed the differences in prognosis between patients with high and low expression of RUNX1 via the Kaplan–Meier method and Cox regression. Gene set enrichment analysis (GSEA) was performed to explore the mechanisms of RUNX1 in ccRCC. Results The expression of RUNX1 in ccRCC tissues was significantly higher than that in normal tissues. High expression of RUNX1 was significantly associated with gender (p = 0.003), clinical stage (p < 0.001), tissue infiltration (p < 0.001), lymph node metastasis (p = 0.037) and histological grade (p < 0.001). Logistic regression analysis showed that high RUNX1 expression was significantly correlated with gender (OR = 1.71 for male vs. female, p = 0.004), histological grade (OR = 11.61 for grade IV vs. I, p < 0.001), clinical stage (OR = 1.55 for stage III/IV vs. I/II, p = 0.014) and tissue infiltration (OR = 1.54 for positive vs. negative, p = 0.018). Kaplan–Meier survival curves revealed that the prognosis of patients with ccRCC with high RUNX1 expression was worse than that of patients with ccRCC with low RUNX1 expression (p < 0.001). Univariate Cox regression analysis showed that high RUNX1 expression was strongly correlated with poor prognosis (HR = 1.60, 95% CI [1.31–1.97], p < 0.001). In addition, high expression of RUNX1 was an independent prognostic factor for poor overall survival (OS), with an HR of 1.50 (95% CI [1.20–1.87], p < 0.001) in multivariate Cox analysis. GSEA showed that the apoptosis, B cell receptor signalling pathway, calcium signalling pathway, chemokine signalling pathway, JAK/STAT signalling pathway, MAPK signalling pathway, p53 signalling pathway, pathways in cancer, T cell receptor signalling pathway, Toll-like receptor signalling pathway, VEGF signalling pathway, and Wnt signalling pathway were significantly enriched in the RUNX1 high-expression phenotype. In conclusion, RUNX1 can be used as a novel prognostic factor and therapeutic target in ccRCC.
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Findlay, Greg M., Lijun Yan, Julia Procter, Virginie Mieulet, and Richard F. Lamb. "A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling." Biochemical Journal 403, no. 1 (March 13, 2007): 13–20. http://dx.doi.org/10.1042/bj20061881.
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The mTOR (mammalian target of rapamycin) signalling pathway is a key regulator of cell growth and is controlled by growth factors and nutrients such as amino acids. Although signalling pathways from growth factor receptors to mTOR have been elucidated, the pathways mediating signalling by nutrients are poorly characterized. Through a screen for protein kinases active in the mTOR signalling pathway in Drosophila we have identified a Ste20 family member (MAP4K3) that is required for maximal S6K (S6 kinase)/4E-BP1 [eIF4E (eukaryotic initiation factor 4E)-binding protein 1] phosphorylation and regulates cell growth. Importantly, MAP4K3 activity is regulated by amino acids, but not the growth factor insulin and is not regulated by the mTORC1 inhibitor rapamycin. Our results therefore suggest a model whereby nutrients signal to mTORC1 via activation of MAP4K3.
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Coleman, Mathew L., and Peter J. Ratcliffe. "Oxygen sensing and hypoxia-induced responses." Essays in Biochemistry 43 (August 10, 2007): 1–16. http://dx.doi.org/10.1042/bse0430001.
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Low cellular oxygenation (hypoxia) represents a significant threat to the viability of affected tissues. Multicellular organisms have evolved a highly conserved signalling pathway that directs many of the changes in gene expression that underpin physiological oxygen homoeostasis. Oxygen-sensing enzymes in this pathway control the activity of the HIF (hypoxia-inducible factor) transcription factor by the direct incorporation of molecular oxygen into the post-translational hydroxylation of specific residues. This represents the canonical hypoxia signalling pathway which regulates a plethora of genes involved in adaptation to hypoxia. The HIF hydroxylases have been identified in other biological contexts, consistent with the possibility that they have other substrates. Furthermore, several intracellular proteins have been demonstrated, directly or indirectly, to be hydroxylated, although the protein hydroxylases responsible have yet to be identified. This chapter will summarize what is currently known about the canonical HIF hydroxylase signalling pathway and will speculate on the existence of other oxygen-sensing enzymes and the role they may play in signalling hypoxia through other pathways.
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Šrámek, Jan, Vlasta Němcová-Fürstová, and Jan Kovář. "Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells." International Journal of Molecular Sciences 22, no. 8 (April 20, 2021): 4285. http://dx.doi.org/10.3390/ijms22084285.
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Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.
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Sun, Zhan-Bin, Shu-Fan Yu, Chu-Lun Wang, and Ling Wang. "cAMP Signalling Pathway in Biocontrol Fungi." Current Issues in Molecular Biology 44, no. 6 (June 4, 2022): 2622–34. http://dx.doi.org/10.3390/cimb44060179.
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Biocontrol is a complex process, in which a variety of physiological and biochemical characteristics are altered. The cAMP signalling pathway is an important signal transduction pathway in biocontrol fungi and consists of several key components. The G-protein system contains G-protein coupled receptors (GPCRs), heterotrimeric G-proteins, adenylate cyclase (AC), cAMP-dependent protein kinase (PKA), and downstream transcription factors (TFs). The cAMP signalling pathway can regulate fungal growth, development, differentiation, sporulation, morphology, secondary metabolite production, environmental stress tolerance, and the biocontrol of pathogens. However, few reviews of the cAMP signalling pathway in comprehensive biocontrol processes have been reported. This work reviews and discusses the functions and applications of genes encoding each component in the cAMP signalling pathway from biocontrol fungi, including the G-protein system components, AC, PKA, and TFs, in biocontrol behaviour. Finally, future suggestions are provided for constructing a complete cAMP signalling pathway in biocontrol fungi containing all the components and downstream effectors involved in biocontrol behavior. This review provides useful information for the understanding the biocontrol mechanism of biocontrol fungi by utilising the cAMP signalling pathway.
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Spormann, Luise, Christiane Rennert, Erik Kolbe, Fritzi Ott, Carolin Lossius, Robert Lehmann, Rolf Gebhardt, Thomas Berg, and Madlen Matz-Soja. "Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver." Cells 9, no. 8 (July 31, 2020): 1817. http://dx.doi.org/10.3390/cells9081817.
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In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.
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Nolan, Aoife A., Nourhan K. Aboud, Walter Kolch, and David Matallanas. "Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling." Genes 12, no. 4 (April 10, 2021): 553. http://dx.doi.org/10.3390/genes12040553.
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Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration.
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Wang, Baojun, Mauricio Barahona, Martin Buck, and Jörg Schumacher. "Rewiring cell signalling through chimaeric regulatory protein engineering." Biochemical Society Transactions 41, no. 5 (September 23, 2013): 1195–200. http://dx.doi.org/10.1042/bst20130138.
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Bacterial cells continuously sense and respond to their environment using their inherent signalling and gene regulatory networks. Cells are equipped with parallel signalling pathways, which can specifically cope with individual input signals, while interconnectivities between pathways lead to an enhanced complexity of regulatory responses that enable sophisticated adaptation. In principle, any cell signalling pathway may be rewired to respond to non-cognate signals by exchanging and recombining their underlying cognate signalling components. In the present article, we review the engineering strategies and use of chimaeric regulatory proteins in cell signalling pathways, especially the TCS (two-component signalling) system in bacteria, to achieve novel customized signalling or regulatory functions. We envisage that engineered chimaeric regulatory proteins can play an important role to aid both forward and reverse engineering of biological systems for many desired applications.
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KOLCH, Walter. "Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions." Biochemical Journal 351, no. 2 (October 10, 2000): 289–305. http://dx.doi.org/10.1042/bj3510289.
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The Ras/Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular-signal-regulated kinase) pathway is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Although the basic regulatory steps have been elucidated, many features of this pathway are only beginning to emerge. This review focuses on the role of protein–protein interactions in the regulation of this pathway, and how they contribute to co-ordinate activation steps, subcellular redistribution, substrate phosphorylation and cross-talk with other signalling pathways.
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Yin, Fei, Tianyi Jiang, and Enrique Cadenas. "Metabolic triad in brain aging: mitochondria, insulin/IGF-1 signalling and JNK signalling." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 101–5. http://dx.doi.org/10.1042/bst20120260.
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Mitochondria generate second messengers, such as H2O2, that are involved in the redox regulation of cell signalling and their function is regulated by several cytosolic signalling pathways. IIS [insulin/IGF1 (insulin-like growth factor 1) signalling] in the brain proceeds mainly through the PI3K (phosphatidylinositol 3-kinase)–Akt (protein kinase B) pathway, which is involved in the regulation of synaptic plasticity and neuronal survival via the maintenance of the bioenergetic and metabolic capacities of mitochondria. Conversely, the JNK (c-Jun N-terminal kinase) pathway is induced by increased oxidative stress and JNK translocation to the mitochondrion results in impairment of energy metabolism. Moreover, IIS and JNK signalling interact with and antagonize each other. This review focuses on functional outcomes of a metabolic triad that entails the co-ordination of mitochondrial function (energy transducing and redox regulation), IIS and JNK signalling, in the aging brain and in neurodegenerative disorders, such as Alzheimer's disease.
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Keshishian, Erika A., and Aaron M. Rashotte. "Plant cytokinin signalling." Essays in Biochemistry 58 (September 15, 2015): 13–27. http://dx.doi.org/10.1042/bse0580013.
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Cytokinin is an essential plant hormone that is involved in a wide range of plant growth and developmental processes which are controlled through its signalling pathway. Cytokinins are a class of molecules that are N6-substituted adenine derivatives, such as isopentenyl adenine, and trans- and cis-zeatin, which are common in most plants. The ability to perceive and respond to cytokinin occurs through a modified bacterial two-component pathway that functions via a multi-step phosphorelay. This cytokinin signalling process is a crucial part of almost all stages of plant life, from embryo patterning to apical meristem regulation, organ development and eventually senescence. The cytokinin signalling pathway involves the co-ordination of three types of proteins: histidine kinase receptors to perceive the signal, histidine phosphotransfer proteins to relay the signal, and response regulators to provide signal output. This pathway contains both positive and negative elements that function in a complex co-ordinated manner to control cytokinin-regulated plant responses. Although much is known about how this cytokinin signal is perceived and initially regulated, there are still many avenues that need to be explored before the role of cytokinin in the control of plant processes is fully understood.
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Scott, Alice, and Harry Mellor. "VEGF receptor trafficking in angiogenesis." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1184–88. http://dx.doi.org/10.1042/bst0371184.
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The intracellular trafficking of receptors provides a way to control the overall sensitivity of a cell to receptor stimulation. These sorting pathways are also used to shape the balance of signals that are generated in response to receptor activation. The major pro-angiogenic growth factor receptor is VEGFR2 (vascular endothelial growth factor 2). VEGFR2 activates a very similar set of signalling pathways to other RTKs (receptor tyrosine kinases); however, its intracellular trafficking is very different. Furthermore, VEGFR2 can form a complex with a range of different angiogenic regulators that in turn regulate the trafficking of VEGFR2 through the endosomal pathway. This regulated trafficking of VEGFR2 has important consequences for angiogenic signalling and is a clear demonstration of how the endosomal pathway plays a critical role in connecting receptor signalling pathways to cellular events.
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Davie, J. R., S. K. Samuel, V. A. Spencer, L. T. Holth, D. N. Chadee, C. P. Peltier, J. M. Sun, H. Y. Chen, and J. A. Wright. "Organization of chromatin in cancer cells: role of signalling pathways." Biochemistry and Cell Biology 77, no. 4 (August 25, 1999): 265–75. http://dx.doi.org/10.1139/o99-044.
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The role of mechanical and chemical signalling pathways in the organization and function of chromatin is the subject of this review. The mechanical signalling pathway consists of the tissue matrix system that links together the three-dimensional skeletal networks, the extracellular matrix, cytoskeleton, and nuclear matrix. Intermediate filament proteins are associated with nuclear DNA, suggesting that intermediate filaments may have a role in the organization of chromatin. In human hormone-dependent breast cancer cells, the interaction between cytokeratins and chromatin is regulated by estrogens. Transcription factors, histone acetyltransferases, and histone deacetylases, which are associated with the nuclear matrix, are components of the mechanical signalling pathway. Recently, we reported that nuclear matrix-bound human and chicken histone deacetylase 1 is associated with nuclear DNA in situ, suggesting that histone deacetylase has a role in the organization of nuclear DNA. Chemical signalling pathways such as the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway stimulate the activity of kinases that modify transcription factors, nonhistone chromosomal proteins, and histones. The levels of phosphorylated histones are increased in mouse fibroblasts transformed with oncogenes, the products of which stimulate the Ras/MAPK pathway. Histone phosphorylation may lead to decondensation of chromatin, resulting in aberrant gene expression.Key words: histone acetylation, histone phosphorylation, nuclear matrix, cytoskeleton, histone deacetylase, cancer.