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  • 1
    Language: English
    In: The Journal of biological chemistry, 27 April 2012, Vol.287(18), pp.14325-35
    Description: Under conditions of reduced mitogen or nutritional substrate levels, the serine/threonine kinase target of rapamycin can augment the nuclear content of distinct transcription factors and promote the induction of stress response genes. In its latent (i.e., unphosphorylated) form, the transcription factor STAT1 regulates a subset of genes involved in immune modulation and apoptosis. Based on previous work indicating a functional relationship between mammalian target of rapamycin (mTOR) and the nuclear content of latent STAT1, we investigated the mechanism by which mTOR controls STAT1 nuclear import. By fluorescence confocal microscopy, inactivation of mTOR with rapamycin promoted the nuclear translocation of unphosphorylated STAT1, but not that of a STAT1 mutant incapable of binding its nuclear import adaptor karyopherin-α1 (KPNA1). By immunoprecipitation, KPNA1 was physically associated with mTOR and STAT1 in a complex that translocated to the nucleus in response to rapamycin. Although mTOR...
    Subject(s): Cell Nucleus -- Metabolism ; Tor Serine-Threonine Kinases -- Metabolism ; Alpha Karyopherins -- Metabolism
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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  • 2
    Language: English
    In: The Journal of biological chemistry, 03 February 2017, Vol.292(5), pp.1899-1909
    Description: Autophagy involves the lysosomal degradation of cytoplasmic contents for regeneration of anabolic substrates during nutritional or inflammatory stress. Its initiation occurs rapidly after inactivation of the protein kinase mammalian target of rapamycin (mTOR) (or mechanistic target of rapamycin), leading to dephosphorylation of Unc-51-like kinase 1 (ULK1) and autophagosome formation. Recent studies indicate that mTOR can, in parallel, regulate the activity of stress transcription factors, including signal transducer and activator of transcription-1 (STAT1). The current study addresses the role of STAT1 as a transcriptional suppressor of autophagy genes and autophagic activity. We show that STAT1-deficient human fibrosarcoma cells exhibited enhanced autophagic flux as well as its induction by pharmacological inhibition of mTOR. Consistent with enhanced autophagy initiation, ULK1 mRNA and protein levels were increased in STAT1-deficient cells. By chromatin immunoprecipitation, STAT1 bound...
    Subject(s): Apoptosis ; Autophagy ; Mammalian Target of Rapamycin (Mtor) ; Proteolysis ; Signal Transducers and Activators of Transcription 1 (Stat1) ; Autophagy -- Physiology ; Autophagy-Related Protein-1 Homolog -- Biosynthesis ; Gene Expression Regulation, Enzymologic -- Physiology ; Intracellular Signaling Peptides and Proteins -- Biosynthesis ; Stat1 Transcription Factor -- Metabolism
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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  • 3
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e33984
    Description: The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.
    Subject(s): Research Article ; Biology ; Medicine ; Immunology ; Respiratory Medicine
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 01 May 2012, Vol.188(9), pp.4535-42
    Description: Acute lung injury during bacterial infection is associated with neutrophilic inflammation, epithelial cell apoptosis, and disruption of the alveolar-capillary barrier. TLR4 is required for lung injury in animals exposed to bacterial LPS and initiates proinflammatory responses in part via the transcription factor NF-κB. Ligation of TLR4 also initiates a proapoptotic response by activating IFN-β and STAT1-dependent genes. We recently demonstrated that mammalian target of rapamycin (mTOR), a key controller of cell growth and survival, can physically interact with STAT1 and suppress the induction of STAT1-dependent apoptosis genes. We therefore hypothesized that the mTOR inhibitor rapamycin would increase LPS-induced apoptosis and lung injury in vivo. Rapamycin increased lung injury and cellular apoptosis in C57BL/6J mice exposed to intratracheal LPS for 24 h. Rapamycin also augmented STAT1 activation, and the induction of STAT1-dependent genes that mediate cellular apoptosis (i.e., Fas, caspase-3)....
    Subject(s): Acute Lung Injury -- Immunology ; Apoptosis -- Drug Effects ; Lipopolysaccharides -- Toxicity ; Tor Serine-Threonine Kinases -- Immunology ; Toll-Like Receptor 4 -- Immunology
    ISSN: 0022-1767
    E-ISSN: 1550-6606
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  • 5
    Language: German
    Description: eingereicht von Kristof Arnold Zusammenfassungen in Deutsch und Englisch Abweichender Titel laut Übersetzung des Verfassers/der Verfasserin Karl-Franzens-Universität Graz, Diplomarbeit, 2017 (VLID)1825322
    Subject(s): Bergsteigen ; Schulsport ; Risikomanagement
    Source: unipub Repository (University of Graz)
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  • 6
    Language: English
    In: Cancer research, 15 October 2017, Vol.77(20), pp.5491-5502
    Description: Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the or tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming mutation-bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic...
    Subject(s): Lymphangioleiomyomatosis -- Genetics ; Myocytes, Smooth Muscle -- Physiology ; Pluripotent Stem Cells -- Physiology
    ISSN: 0008-5472
    E-ISSN: 1538-7445
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  • 7
    Language: English
    In: The Journal of clinical investigation, February 2015, Vol.125(2), pp.752-68
    Description: The phagocytosis of apoptotic cells and associated vesicles (efferocytosis) by DCs is an important mechanism for both self tolerance and host defense. Although some of the engulfment ligands involved in efferocytosis have been identified and studied in vitro, the contributions of these ligands in vivo remain ill defined. Here, we determined that during Mycobacterium tuberculosis (Mtb) infection, the engulfment ligand annexin1 is an important mediator in DC cross-presentation that increases efferocytosis in DCs and intrinsically enhances the capacity of the DC antigen-presenting machinery. Annexin1-deficient mice were highly susceptible to Mtb infection and showed an impaired Mtb antigen-specific CD8+ T cell response. Importantly, annexin1 expression was greatly downregulated in Mtb-infected human blood monocyte-derived DCs, indicating that reduction of annexin1 is a critical mechanism for immune evasion by Mtb. Collectively, these data indicate that annexin1 is essential in immunity to...
    Subject(s): Cross-Priming ; Immunity, Cellular ; Phagocytosis ; Annexin A1 -- Immunology ; Dendritic Cells -- Immunology ; Mycobacterium Tuberculosis -- Immunology ; Tuberculosis -- Immunology
    ISSN: 0021-9738
    E-ISSN: 1558-8238
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  • 8
    Language: English
    In: Critical care (London, England), 22 October 2013, Vol.17(5), pp.R251
    Description: Ventilator-associated respiratory infection (VARI) is an important cause of morbidity in critically-ill patients. Clinical trials performed in heterogeneous populations have suggested there are limited benefits from invasive diagnostic testing to identify patients at risk or to target antimicrobial therapy. However, multiple patient subgroups (for example, immunocompromised, antibiotic-treated) have traditionally been excluded from randomization. We hypothesized that a prospective surveillance study would better identify patients with suspected VARI (sVARI) at high risk for adverse clinical outcomes, and who might be specifically targeted in future trials. We performed a prospective observational study in all patients ventilated for greater than 48 hours. sVARI was identified by surveillance for changes in white blood cell count, temperature, sputum, and/or new chest X-ray infiltrates. Indices of disease co-morbidity, as well as mortality, duration of mechanical ventilation, and length of hospital or ICU stay were correlated with sVARI. Of 1806 patients admitted to the ICU over 14 months, 267 were ventilated for greater than 48 hours, and 77 developed sVARI. Incidence of sVARI was associated with iatrogenic immunosuppression or admission for respiratory illness. Any sVARI, whether suspected ventilator-associated pneumonia (sVAP) or ventilator-associated tracheobronchitis (sVAT), was associated with increased length of stay and duration of mechanical ventilation. Clinical surveillance for sVARI identifies patients at risk for increased morbidity. Iatrogenically immunosuppressed patients, a subgroup previously excluded from randomized clinical trials, represent a growing proportion of the critically-ill at risk for sVARI who might be targeted for future investigations on diagnostic or therapeutic modalities.
    Subject(s): Critical Illness ; Intensive Care Units ; Respiration, Artificial -- Adverse Effects ; Respiratory Tract Infections -- Etiology
    ISSN: 1364-8535
    E-ISSN: 1466-609X
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  • 9
    Language: English
    In: Journal of Biological Chemistry, 03/16/2001, Vol.276(11), pp.8445-8452
    Description: Inducible nitric-oxide synthase (iNOS) is an important signaling protein involved in the regulation of biological processes (e.g. vasodilation, inflammation) and is subject to transcriptional regulation by cytokines and lipopolysaccharide (LPS). Full activation of the human iNOS (hiNOS) promoter by cytokines (i.e., tumor necrosis factor- alpha , interleukin-1 beta , interferon- gamma (IFN- gamma )) required downstream and upstream nuclear factor- Kappa B (-115, -8283) and activator protein-1 (AP-1) (-5115, -5301) transcription factor binding sites. Human lung epithelial (A549) cells were transiently transfected with luciferase reporter plasmids containing an 8.3-kilobase human iNOS promoter to examine the molecular signaling events necessary for hiNOS transcriptional activation. The combination of LPS and IFN- gamma , but neither alone, increased hiNOS promoter activity 28-fold, in a reaction requiring two critical AP-1 (JunD super(.)Fra-2) promoter binding sites. Mitogen-activated protein kinases (MAPKs) were assessed as potential activators of AP-1 and the hiNOS promoter. Both pharmacological and molecular inhibitors of the extracellular signal-related kinase (ERK) and p38 pathways reduced cytokine mixture (CM)- and LPS/IFN- gamma -induced promoter activation. By gel retardation analysis, the addition of MAP/ERK kinase-1 and p38 inhibitors significantly diminished AP-1 binding in both CM- and LPS/IFN- gamma -stimulated cells. Thus, p38- and ERK-dependent pathways, through effects on the AP-1 complex, activate the hiNOS promoter in cells stimulated with CM or LPS/IFN- gamma .
    Subject(s): Gene Regulation ; MAP Kinase ; Nitric-Oxide Synthase ; Tumor Necrosis Factor-^a ; Interleukin 1 ; ^G-Interferon ; ^AAP-1 Protein ; Lipopolysaccharides ; Nf-^Kb Protein ; Erk Protein ; P38 Protein ; Gene Regulation ; Man ; Erk Protein ; Nf- Kappa B Protein ; Man ; P38 Protein;
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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  • 10
    Language: English
    In: American journal of physiology. Renal physiology, September 2011, Vol.301(3), pp.F554-64
    Description: The expression and activation of the Ste20-like kinase, SLK, is increased during renal development and recovery from ischemic acute renal failure. SLK promotes apoptosis, and during renal injury and repair, transcriptional induction or posttranscriptional control of SLK may, therefore, regulate cell survival. SLK contains protein interaction (coiled-coil) domains, suggesting that posttranslational homodimerization may also modulate SLK activity. We therefore expressed coiled-coil regions in the C-terminal domain of SLK as fusion proteins and demonstrated their homodimerization. By gel-filtration chromatography, endogenous and heterologously expressed SLK were detected in a macromolecular protein complex. To test the role of homodimerization in kinase activation, we constructed a fusion protein consisting of the SLK catalytic domain (amino acids 1-373) and a modified FK506 binding protein, Fv (Fv-SLK 1-373). Addition of AP20187 (an analog of FK506) enhanced the homodimerization of Fv-SLK...
    Subject(s): Kidney -- Metabolism ; Protein Multimerization -- Physiology ; Protein-Serine-Threonine Kinases -- Metabolism
    ISSN: 1522-1466
    ISSN: 00029513
    E-ISSN: 1522-1466
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