1,721,001 research outputs found
CMTM4 as a new partner for IL‐17 receptor: Adding a piece in the puzzle of IL17‐driven diseases
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GSK-3 beta inhibition - At the crossroad between Akt and mTOR constitutive activation to enhance cyclin D1 protein stability in mantle cell lymphoma
No full textStrategies able to downregulate the aberrant expression of cyclin D1 may prove of therapeutic relevance in cancer patients. This is particularly true for mantle cell lymphoma (MCL) in which cyclin D1 is overexpressed as a consequence of the t(11;14)(q13;q32) translocation. We have recently demonstrated that an increased cyclin D1 stability also contributes to the high levels of this protein observed in MCL cells. This effect is mediated by a constitutive activation of PI3-K/Akt, which keeps GSK-3β inhibited. Here we show that inhibition of PI3-K/Akt induces a 40% decrease of cyclin D1 half-life as a result of accumulation of the dephosphorylated/active form of GSK-3β within the nucleus, where this kinase can phosphorylate cyclin D1 on Thr286 thereby promoting its nuclear export. Translocation of cyclin D1 into the cytoplasm is mediated by the nuclear exportin CRM1, whose association with cyclin D1 increases following PI3-K/Akt inhibition. Notably, rapamycin downregulated GSK-3β Ser9 phosphorylation with concurrent nuclear export of cyclin D1 only in MCL cells in which GSK-3β is under the control of mTOR. These findings suggest that the ability to downregulate cyclin D1 through GSK-3β may identify subsets of MCL patients who may benefit from the treatment with mTOR inhibitors and stimulate further studies to assess whether the inability to affect GSK-3β activity may constitute a clinically relevant resistance factor to mTOR inhibitors. ©2008 Landes Bioscience
Damage-associated molecular patterns modulation by microrna: Relevance on immunogenic cell death and cancer treatment outcome
No full textImmunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy
Interplay among viral antigens, cellular pathways and tumor microenvironment in the pathogenesis of EBV-driven lymphomas
No full textEpstein-Barr virus (EBV) is a ubiquitous human γ-herpes virus that has established an elegant strategy to persist as a life-long asymptomatic infection in memory B lymphocytes. EBV has potent transforming properties for B lymphocytes and it is pathogenically associated with a variety of lymphomas of B or NK/T cell origin. The viral latency programs expressed can hijack or deregulate cellular pathways critical for cell proliferation and survival, while impairing anti-viral immune responses. Similar effects may also be induced by EBV-encoded micro-RNAs, which may have a pathogenic role particularly in lymphomas showing a restricted expression of viral proteins. Of note, recent data have challenged the view that only the EBV latency is relevant for lymphomagenesis, suggesting that lytic EBV replication may also contribute to the development of EBV-associated lymphoproliferations. The recent advances in the elucidation of the mechanisms underlying EBV-induced cell transformation and immune evasion are providing the rationale for innovative and tailored treatment approaches for EBV-driven lymphomas. © 2013 Elsevier Ltd
Phospholipid Scramblase 1 Sensitizes Mantle Cell Lymphoma to Apoptosis Induced by Several Drugs
No full textDifferential expression of RNA-binding proteins in airway epithelium in chronic lung inflammation
No full textIntroduction: Posttranscriptional gene regulation (PTR) critically controls inflammation by modulating messenger RNA (mRNA) turn over and translation rates. RNA-binding proteins (RBP) coordinate PTR by binding to conserved sequences of targeted mRNAs. The majority of pathogenetic genes expressed in immune and structural cells in chronic lung inflammation are amenable to RBP-coordinated PTR, yet the role of RBPs in this setting remains elusive.
Objectives: The overall aim of the study is to characterize the expression pattern and activation state of a panel of oxidative stress-regulated RBPs in patients with asthma, COPD and in relevant control subjects. RBP expression was evaluated by: immunohistochemistry (IHC) with validated antibodies using standard immunoper oxidase techniques on formalin-fixed, paraffin embedded tissues obtained from bronchial mucosa and peripheral lung samples of well-phenotyped, mild to moderate stable COPD patients (n=10), compared with age/gender/smoking history-matched smokers with nor mal lung function (n=12); by Western blot (WB) and real-time PCR in the human airway epithelial cell line BEAS-2B stimulated with H2O2 (100 lM, 24 h, n=3); by real-time PCR in PBMC of COPD patients (n=5)/controls (n=7) characterized as for the IHC study. Study was approved by local Ethics Committees. Statistical significance was assessed by analysis of variance and Kruskal–Wallis tests.
Results: We identified by IHC three of the RBPs mainly regulating inflammatory transcripts: tristetraprolin (TTP), Hu antigen R (HuR) and heterogeneous nuclear ribonucleoprotein D (HnRNPD, also ter med AUF-1) in the airways’ samples of COPD patients and controls. Expression of AUF-1, an RBP functionally linked to accelerated decay of inflammatory transcripts, was significantly (P=.015) lower in bronchial epithelium of COPD samples vs. controls, while remaining comparable between groups in bronchiolar epithelium, glandular cells and alveolar macrophages. Decreased AUF-1 expression was also found by WB analysis of BEAS2B cells treated with H2O2; in PBMC, RBP mRNA levels did not differ between groups
Epstein-Barr virus and telomerase: from cell immortalization to therapy
Full text linkOvercoming cellular senescence is strictly required for virus-driven tumors, including those associated with Epstein-Barr virus (EBV). This critical step is successfully accomplished by EBV through TERT expression and telomerase activation in infected cells. We herein review the complex interplay between EBV and TERT/telomerase in EBV-driven tumorigenesis. Evidence accumulated so far clearly indicates that elucidation of this issue may offer promising opportunities for the design of innovative treatment modalities for EBV-associated malignancies. Indeed, several therapeutic strategies for telomerase inhibition have been developed and are being investigated in clinical trials. In this respect, our recent finding that TERT inhibition sensitizes EBV+ lymphoma cells to antivirals through activation of EBV lytic replication is particularly promising and provides a rationale for the activation of clinical studies aimed at assessing the effects of combination therapies with TERT inhibitors and antivirals for the treatment of EBV-associated malignancies
Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins
No full textRetinoic acid (RA) arrests the growth of EBV-immortalized lymphoblastoid B cell lines (LCLs) by upregulating the cyclin-dependent kinase inhibitor p27 Kip1. Here, we show that in LCLs, RA inhibits ubiquitination and proteasome-dependent degradation of p27Kip1, a phenomenon that is associated with downregulation of Thr187 phosphorylation of the protein, whereas the phosphorylation on Ser10 is unaffected. Furthermore, we demonstrate that RA downregulates the expression of the p45Skp2 and Cks1 proteins, two essential components of the SCFSkp2 ubiquitin ligase complex that target p27Kip1 for degradation. Downregulation of p45Skp2 and Cks1 occurs before the onset of growth arrest and is due to enhanced proteasome-mediated proteolysis of these proteins. Moreover, overexpression of p45Skp2 in DG75 cells prevents p27Kip1 protein accumulation and promotes resistance to the antiproliferative effects of RA. Treatment with Leptomycin B (LMB) blocked the translocation of p27 Kip1 to the cytoplasm and prevented its degradation, indicating that CRM1-dependent nuclear export is required for p27Kip1 degradation. The shuttle protein p38Jab1, however, does not accumulate in the nucleus upon LMB treatment, nor does it interact with p27Kip1. Conversely, p45Skp2 is associated with p27Kip1 both in the nucleus and in the cytoplasm, accumulating within the nuclei after exposure to LMB and co-localizing with the exportin CRM1, suggesting a possible involvement of p45Skp2 in CRM1-dependent nuclear export of p27Kip1. These results indicate that downregulation of p45Skp2 is a key element underlying RA-induced p27Kip1 stabilization in B cells, resulting in an impaired targeting of the protein to the ubiquitin-proteasome pathway and probably contributing to the nuclear accumulation of p27 Kip1. © 2005 Nature Publishing Group All rights reserved
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