Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular ...countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation.
Mouse models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of signal transducers and activators of ...transcription 3 (STAT3).
To investigate the expression of IL6/phosphorylated STAT3 (p-STAT3)/suppressor of cytokine signalling 3 (SOCS3) in biopsy specimens from patients with ulcerative colitis (UC) and UC-related colorectal cancer (CRC) progression.
Biopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with low-grade dysplasia (LGD) (n=9), UC with high-grade dysplasia (HGD) (n=7), UC-CRC (n=11) and sporadic CRC (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of IL6, p-STAT3 and SOCS3 was determined immunohistochemically.
Patients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls (strong positive IL6: 53.6%, 11.1% and 0%, respectively; p-STAT3: 64.3%, 22.2% and 11.1%, respectively; all p<or=0.012). SOCS3-positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In dysplasia and cancer, significantly more epithelial cells expressed IL6 and p-STAT3 compared with controls (strong positive IL6: 72.7% and 0% respectively; p-STAT3: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of SOCS3-positive cells in this progression reduced (LGD 33.3%; HGD 14.3%; UC-CRC 9.1%). In addition, methylation of the SOCS3 gene was detected in epithelial cells from UC-CRC biopsy specimens.
The importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.
The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate ...Wnt/β‐catenin signalling through their interaction with β‐catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/β‐catenin signalling. We show that YAP and TAZ, the transcriptional co‐activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of β‐catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to β‐catenin, thereby suppressing Wnt‐target gene expression, and that the Hippo pathway‐stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP‐mediated inhibition of Wnt/β‐catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of β‐catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of β‐catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of β‐catenin.
The Hippo pathway effector YAZ is found to bind β‐catenin and prevents its nuclear translocation. The resulting downregulation of Wnt signal transduction provides a new example for intersection of Hippo and Wnt signalling, two key regulatory pathways in animal development
Signaling Theory: A Review and Assessment Connelly, Brian L.; Certo, S. Trevis; Ireland, R. Duane ...
Journal of Management,
01/2011, Letnik:
37, Številka:
1
Book Review, Journal Article
Recenzirano
Signaling theory is useful for describing behavior when two parties (individuals or organizations) have access to different information. Typically, one party, the sender, must choose whether and how ...to communicate (or signal) that information, and the other party, the receiver, must choose how to interpret the signal. Accordingly, signaling theory holds a prominent position in a variety of management literatures, including strategic management, entrepreneurship, and human resource management. While the use of signaling theory has gained momentum in recent years, its central tenets have become blurred as it has been applied to organizational concerns. The authors, therefore, provide a concise synthesis of the theory and its key concepts, review its use in the management literature, and put forward directions for future research that will encourage scholars to use signaling theory in new ways and to develop more complex formulations and nuanced variations of the theory.
Much of our current knowledge on the mechanisms by which Ca²⁺ signals are generated in photosynthetic eukaryotes comes from studies of a relatively small number of model species, particularly green ...plants and algae, revealing some common features and notable differences between 'plant' and 'animal' systems. Physiological studies from a broad range of algal cell types have revealed the occurrence of animal-like signalling properties, including fast action potentials and fast propagating cytosolic Ca²⁺ waves. Genomic studies are beginning to reveal the widespread occurrence of conserved channel types likely to be involved in Ca²⁺ signalling. However, certain widespread 'ancient' channel types appear to have been lost by certain groups, such as the embryophytes. More recent channel gene loss is also evident from comparisons of more closely related algal species. The underlying processes that have given rise to the current distributions of Ca²⁺ channel types include widespread retention of ancient Ca²⁺ channel genes, horizontal gene transfer (including symbiotic gene transfer and acquisition of bacterial genes), gene loss and gene expansion within taxa. The assessment of the roles of Ca²⁺ channel genes in diverse physiological, developmental and life history processes represents a major challenge for future studies.
SUMMARY
Plant response to drought stress includes systems for intracellular regulation of gene expression and signaling, as well as inter‐tissue and inter‐organ signaling, which helps entire plants ...acquire stress resistance. Plants sense water‐deficit conditions both via the stomata of leaves and roots, and transfer water‐deficit signals from roots to shoots via inter‐organ signaling. Abscisic acid is an important phytohormone involved in the drought stress response and adaptation, and is synthesized mainly in vascular tissues and guard cells of leaves. In leaves, stress‐induced abscisic acid is distributed to various tissues by transporters, which activates stomatal closure and expression of stress‐related genes to acquire drought stress resistance. Moreover, the stepwise stress response at the whole‐plant level is important for proper understanding of the physiological response to drought conditions. Drought stress is sensed by multiple types of sensors as molecular patterns of abiotic stress signals, which are transmitted via separate parallel signaling networks to induce downstream responses, including stomatal closure and synthesis of stress‐related proteins and metabolites. Peptide molecules play important roles in the inter‐organ signaling of dehydration from roots to shoots, as well as signaling of osmotic changes and reactive oxygen species/Ca2+. In this review, we have summarized recent advances in research on complex plant drought stress responses, focusing on inter‐tissue signaling in leaves and inter‐organ signaling from roots to shoots. We have discussed the mechanisms via which drought stress adaptations and resistance are acquired at the whole‐plant level, and have proposed the importance of quantitative phenotyping for measuring plant growth under drought conditions.
Significance Statement
This review focuses on inter‐tissue signaling, inter‐organ signaling, and stress sensing in complex drought stress responses and tolerance, in which molecular patterns of stress signals are sensed by different sensors and transmitted to other tissues and organs to induce stress responses in total. Recent progress in quantitative phenotyping under drought conditions is also discussed to understand the whole system of complex drought responses and tolerance.
Hepatocellular carcinoma (HCC) is the third leading cause of the cancer‐related death in the world. Human amniotic mesenchymal stem cells (hAMSCs) have been characterized with a pluripotency, low ...immunogenicity and no tumorigenicity. Especially, the immunosuppressive and anti‐inflammatory effects of hAMSCs make them suitable for treating HCC. Here, we reported that hAMSCs administrated by intravenous injection significantly inhibited HCC through suppressing cell proliferation and inducing cell apoptosis in tumour‐bearing mice with Hepg2 cells. Cell tracking experiments with GFP‐labelled hAMSCs showed that the stem cells possessed the ability of migrating to the tumorigenic sites for suppressing tumour growth. Importantly, both hAMSCs and the conditional media (hAMSC‐CM) have the similar antitumour effects in vitro, suggesting that hAMSCs‐derived cytokines might be involved in their antitumour effects. Antibody array assay showed that hAMSCs highly expressed dickkopf‐3 (DKK‐3), dickkopf‐1 (DKK‐1) and insulin‐like growth factor‐binding protein 3 (IGFBP‐3). Furthermore, the antitumour effects of hAMSCs were further confirmed by applications of the antibodies or the specific siRNAs of DKK‐3, DKK‐1 and IGFBP‐3 in vitro. Mechanically, hAMSCs‐derived DKK‐3, DKK‐1 and IGFBP‐3 markedly inhibited cell proliferation and promoted apoptosis of Hepg2 cells through suppressing the Wnt/β‐catenin signalling pathway and IGF‐1R‐mediated PI3K/AKT signalling pathway, respectively. Taken together, our study demonstrated that hAMSCs possess significant antitumour effects in vivo and in vitro and might provide a novel strategy for HCC treatment clinically.
Mitotic and mitogenic Wnt signalling Niehrs, Christof; Acebron, Sergio P
The EMBO journal,
June 13, 2012, Letnik:
31, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Canonical Wnt signalling plays an important role in development, tissue homeostasis, and cancer. At the cellular level, canonical Wnt signalling acts by regulating cell fate, cell growth, and cell ...proliferation. With regard to proliferation, there is increasing evidence for a complex interaction between canonical Wnt signalling and the cell cycle. Mitogenic Wnt signalling regulates cell proliferation by promoting G1 phase. In mitosis, components of the Wnt signalling cascade function directly in spindle formation. Moreover, Wnt signalling is strongly activated in mitosis, suggesting that ‘mitotic Wnt signalling’ plays an important role to orchestrate a cell division program. Here, we review the complex interplay between Wnt signalling and the cell cycle.
This contribution from Christof Niehrs and Sergio Acebron summarizes the role of Wnt signals during G1 phase and highlights functional activities of distinct pathway components during mitosis.
Background and Purpose
Asthma is a heterogenous disease strongly associated with inflammation that has many different causes and triggers. Current asthma treatments target symptoms such as ...bronchoconstriction and airway inflammation. Despite recent advances in biological therapies, there remains a need for new classes of therapeutic agents with novel, upstream targets. The proteinase‐activated receptor‐2 (PAR2) has long been implicated in allergic airway inflammation and asthma and it remains an intriguing target for novel therapies. Here, we describe the actions of C781, a newly developed low MW PAR2 biased antagonist, in vitro and in vivo in the context of acute allergen exposure.
Experimental Approach
A human bronchial epithelial cell line expressing PAR2 (16HBE14o‐ cells) was used to evaluate the modulation in vitro, by C781, of physiological responses to PAR2 activation and downstream β‐arrestin/MAPK and Gq/Ca2+ signalling. Acute Alternaria alternata sensitized and challenged mice were used to evaluate C781 as a prophylactically administered modulator of airway hyperresponsiveness, inflammation and mucus overproduction in vivo.
Key Results
C781 reduced in vitro physiological signalling in response to ligand and proteinase activation. C781 effectively antagonized β‐arrestin/MAPK signalling without significant effect on Gq/Ca2+ signalling in vitro. Given prophylactically, C781 modulated airway hyperresponsiveness, airway inflammation and mucus overproduction of the small airways in an acute allergen‐challenged mouse model.
Conclusion and Implications
Our work demonstrates the first biased PAR2 antagonist for β‐arrestin/MAPK signalling. C781 is efficacious as a prophylactic treatment for allergen‐induced airway hyperresponsiveness and inflammation in mice. It exemplifies a key pharmacophore for PAR2 that can be optimized for clinical development.
Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before bone metastases develop. Treatment for bone metastases is not ...curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1β stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis.
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