Search results for "signal transduction."

Prediction of Specific TCR-Peptide Binding From Large Dictionaries of TCR-Peptide Pairs

2019

Abstract The T cell repertoire is composed of T cell receptors (TCR) selected by their cognate MHC-peptides and naive TCR that do not bind known peptides. While the task of distinguishing a peptide-binding TCR from a naive TCR unlikely to bind any peptide can be performed using sequence motifs, distinguishing between TCRs binding different peptides requires more advanced methods. Such a prediction is the key for using TCR repertoires as disease-specific biomarkers. We here used large scale TCR-peptide dictionaries with state-of-the-art natural language processing (NLP) methods to produce ERGO (pEptide tcR matchinG predictiOn), a highly specific classifier to predict which TCR binds to which…

The NG2 Proteoglycan Protects Oligodendrocyte Precursor Cells against Oxidative Stress via Interaction with OMI/HtrA2.

2015

The NG2 proteoglycan is characteristically expressed by oligodendrocyte progenitor cells (OPC) and also by aggressive brain tumours highly resistant to chemo- and radiation therapy. Oligodendrocyte-lineage cells are particularly sensitive to stress resulting in cell death in white matter after hypoxic or ischemic insults of premature infants and destruction of OPC in some types of Multiple Sclerosis lesions. Here we show that the NG2 proteoglycan binds OMI/HtrA2, a mitochondrial serine protease which is released from damaged mitochondria into the cytosol in response to stress. In the cytosol, OMI/HtrA2 initiates apoptosis by proteolytic degradation of anti-apoptotic factors. OPC in which NG…

EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells.

2015

KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer (CRC) patients. However, conflicting data exist regarding the variable response to EGFR-targeted therapy. The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations. Cells harboring a single KRASG13D allele showed the most tumorigenic profile, with constitutive activation of the downstream pathway, rendering them EGF-unresponsive. Conversely, KRASA146T cells showed a full EGF-response in terms of signal transduction pathways, cell proliferation, migration or adhesion. Moreover, the global acetylome of CRC cells was al…

Mucins as a New Frontier in Pulmonary Fibrosis

2019

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 3–5 years after diagnosis. Recent evidence identifies mucins as key effectors in cell growth and tissue remodeling processes compatible with the processes observed in IPF. Mucins are classified in two groups depending on whether they are secreted (secreted mucins) or tethered to cell membranes (transmembrane mucins). Secreted mucins (MUC2, MUC5AC, MUC5B, MUC6-8 and MUC19) are released to the extracellular medium and recent evidence has shown that a promoter polymorphism in the secreted mucin MUC5B is associated with IPF risk. Otherwise, transmembrane mucins (MUC1, MUC3,…

Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model

2015

ABSTRACT Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apopto…

A minireview on NHE1 inhibitors. A rediscovered hope in oncohematology.

2015

Background: Na+/H+ exchanger-1 (NHE-1) is involved in pH regulation and is up-regulated in different malignancies. Activation of NHE-1 is one way for allowing cells to avoid intracellular acidification and protect them against apoptosis. Inhibitors of NHE-1 are able to decrease intracellular pH and induce apoptosis. Some statins can also act by partial inhibition of NHE-1. This review presents progress in understanding the mechanisms of action of these inhibitors, connections with certain genetic mutations and acquired treatment resistance, as well as new patents on them. Methods: A MEDLINE search for original and review articles using key terms, Na+/H+ exchanger, leukemia, cariporide, and …

Mutant HRAS as novel target for MEK and mTOR inhibitors.

2015

HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an imp…

P087 Increased wnt ligands expression in M2c macrophages is associated with fibrosis in Stat6 knockout mice

2017

Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps

2013

Background A number of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) are resistant to oral corticosteroids. Mucin 1 (MUC1) shows anti-inflammatory properties, and its cytoplasmic tail (CT) interacts with transcription factors, facilitating their nuclear translocation. Because glucocorticoid receptor (GR) nuclear translocation is key to the anti-inflammatory effect of corticosteroids, we hypothesized that MUC1 is involved in the effectiveness of corticosteroids. Objective To analyze the role of MUC1 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved. Methods Seventy-three patients with CRSwNP took oral…

BCR-ABL as a target for novel therapeutic interventions.

2002

The BCR-ABL oncogene is the result of a reciprocal translocation between the long arms of chromosome 9 and 22 t(9; 22). There is good experimental evidence demonstrating that BCR-ABL is the single causative abnormality in chronic myeloid leukaemia (CML), making it a unique model for the development of molecular targets. In addition to CML, BCR-ABL transcripts can be found in a minority of acute lymphoblastic leukaemias and very rarely in acute myeloid leukaemia (AML). Elucidating the molecular mechanisms and downstream pathways of BCR-ABL has led to the design of several novel therapeutic approaches. In this review, molecular targeting of BCR-ABL will be discussed based on the inhibition of…