Search results for "MAPK"
showing 10 items of 238 documents
Dissecting the different biological effects of oncogenic Ras isoforms in cancer cell lines: Could stimulation of oxidative stress be the one more wea…
2012
Abstract Ras proteins are small GTPase functioning as molecular switches that, in response to particular extracellular signalling, as growth factors, activate a diverse array of intracellular effector cascades regulating cell proliferation, differentiation and apoptosis. Human tumours frequently express Ras proteins (Ha-, Ki-, N-Ras) activated by point mutations which contribute to malignant phenotype, including invasiveness and angiogenesis. Despite the common signalling pathways leading to similar cellular responses, studies clearly demonstrate unique roles of the Ras family members in normal and pathological conditions and the lack of functional redundancy seems to be explainable, at lea…
Research in practice: The impact of interferon-α therapy on immune tolerance
2014
Interferon-α (IFN-α) is the only drug approved for adjuvant therapy of malignant melanoma and is also used in the treatment of hematological and solid tumors. Along with its proven clinical efficacy, IFN-α produces several side effects, particularly with regard to autoimmune disorders. Curious about symptoms of autoimmunity during IFN-α therapy, we asked whether IFN-α directly impacts on immune tolerance. We found that IFN-α does alter the function of tolerogenic dendritic cells (DC) as well as of induced and naturally occurring T-regulatory cells (nTregs). IFN-α blocks the tolerogenic phenotype of DC by inducing maturation and thus preventing the induction of inducible Tregs by DC. It also…
Manganese overload affects p38 MAPK phosphorylation and metalloproteinase activity during sea urchin embryonic development.
2014
Abstract In the marine environment, manganese represents a potential emerging contaminant, resulting from an increased production of manganese-containing compounds. In earlier reports we found that the exposure of Paracentrotus lividus sea urchin embryos to manganese produced phenotypes with no skeleton. In addition, manganese interfered with calcium uptake, perturbed extracellular signal-regulated kinase (ERK) signaling, affected the expression of skeletogenic genes, and caused an increase of the hsc70 and hsc60 protein levels. Here, we extended our studies focusing on the temporal activation of the p38 mitogen-activated protein kinase (p38 MAPK) and the proteolytic activity of metalloprot…
RNF2 Mediates Hepatic Stellate Cells Activation by Regulating ERK/p38 Signaling Pathway in LX-2 Cells
2021
The therapeutic approach of liver fibrosis is still an unsolved clinical problem worldwide. Notably, the accumulation of extracellular matrix (ECM) in the liver is mediated by the production of cytokines and growth factors, such as transforming growth factor-β1 (TGF-β1) in hepatic stellate cells (HSCs). Ring finger protein 2 (RNF2) was identified as the catalytic subunit of polycomb repressive complex 1 (PRC1), mediating the monoubiquitination of histone H2A. In recent years, a growing amount of evidence suggests that RNF2 may play an important role in multiple pathological processes involved in cancer. Here, we explored the role of RNF2 in liver fibrogenesis and its potential mechanisms. T…
Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and G(alpha)q.
2001
Endothelins are potent mitogens that stimulate extracellular signal-regulated kinases (ERK/MAP kinases) through their cognate G-protein-coupled receptors, ET(A) and ET(B). To address the role of post-translational ET receptor modifications such as acylation on ERK activation and to identify relevant downstream effectors coupling the ET receptor to the ERK signaling cascades we have constructed a panel of palmitoylation-deficient ET receptor mutants with differential G(alpha) protein binding capacity. Endothelin-1 stimulation of wild-type ET(A) or ET(B) induced a fivefold to sixfold increase in ERK in COS-7 and CHO cells whereas full-length nonpalmitoylated ET(A) and ET(B) mutants failed to …
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use…
2013
This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in…
Protective dendritic cell responses against listeriosis induced by the short form of the deubiquitinating enzyme CYLD are inhibited by full-length CY…
2015
The deubiquitinating enzyme CYLD is an important tumor suppressor and inhibitor of immune responses. In contrast to full-length CYLD, the immunological function of the naturally occurring short splice variant of CYLD (sCYLD) is insufficiently described. Previously, we showed that DCs, which lack full-length CYLD but express sCYLD, exhibit augmented NF-κB and DC activation. To explore the function of sCYLD in infection, we investigated whether DC-specific sCYLD regulates the pathogenesis of listeriosis. Upon Listeria monocytogenes infection of CD11c-Cre Cyld(ex7/8 fl/fl) mice, infection of CD8α(+) DCs, which are crucial for the establishment of listeriosis in the spleen, was not affected. Ho…
Bis(1H-indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro.
2009
Inhibition of the mutated fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is a promising therapeutic strategy in acute myeloid leukaemia (AML). However, development of resistance to FLT3 tyrosine kinase inhibitors (TKI), such as PKC412A, has been described recently. This observation may have an increasing impact on the duration of response and relapse rates in upcoming clinical trials employing FLT3-TKI. Herein we investigated two representatives of a novel class of FLT3-TKI: Bis(1H-indol-2-yl)methanones. Both compounds effectively induced apoptosis in FLT3-internal tandem duplicate (ITD)-transfected murine myeloid cells and in primary FLT3-ITD positive blasts. Combination of bot…
Divide and rule: The role of ubiquitination in inactivation of the ERK5-MAPK cascade
2014
Recently, we revealed that ubiquitination of MEKK2 and MEKK3 by inhibitor of apoptosis proteins (IAPs) directly disrupts MEK5/ERK5 interaction and subsequently attenuates ERK5 activation. In addition, loss of XIAP promotes human myogenic differentiation in an ERK5-dependent manner. These results reveal another layer of MAPK regulation and a novel role for XIAP in controlling myogenic differentiation.
Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein k…
1999
Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against alpha1 and alpha2 integrin subunits and augmented by activating antibody against beta1 integrin subunit, indicating that both alpha1 beta1 and alpha2 beta1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimens…