| 1. |
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| 2. |
- Charmpilas, Nikolaos, et al.
(författare)
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Acyl-CoA-binding protein (ACBP) : a phylogenetically conserved appetite stimulator
- 2020
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889 .- 2041-4889. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we reported that, in mice, hunger causes the autophagy-dependent release of a protein called acyl-CoA-binding protein or diazepam binding inhibitor (ACBP/DBI) from cells, resulting in an increase in plasma ACBP concentrations. Administration of extra ACBP is orexigenic and obesogenic, while its neutralization is anorexigenic in mice, suggesting that ACBP is a major stimulator of appetite and lipo-anabolism. Accordingly, obese persons have higher circulating ACBP levels than lean individuals, and anorexia nervosa is associated with subnormal ACBP plasma concentrations. Here, we investigated whether ACBP might play a phylogenetically conserved role in appetite stimulation. We found that extracellular ACBP favors sporulation in Saccharomyces cerevisiae, knowing that sporulation is a strategy for yeast to seek new food sources. Moreover, in the nematode Caenorhabditis elegans, ACBP increased the ingestion of bacteria as well as the frequency pharyngeal pumping. These observations indicate that ACBP has a phylogenetically ancient role as a 'hunger factor' that favors food intake.
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| 3. |
- Doffe, Flora, et al.
(författare)
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Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene
- 2021
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 28:5, s. 1477-1492
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Tidskriftsartikel (refereegranskat)abstract
- Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.
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| 4. |
- Dufey, Estefanie, et al.
(författare)
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Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.
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| 5. |
- Eisenberg, Tobias, et al.
(författare)
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Cardioprotection and lifespan extension by the natural polyamine spermidine
- 2016
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 22:12, s. 1428-1438
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Tidskriftsartikel (refereegranskat)abstract
- Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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| 6. |
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| 7. |
- Fezai, Myriam, et al.
(författare)
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Inhibition of colon carcinoma cell migration following treatment with purified venom from lesser weever fish (Trachinus Vipera)
- 2017
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Ingår i: Cellular Physiology and Biochemistry. - : S. Karger AG. - 1015-8987 .- 1421-9778. ; 41:6, s. 2279-2288
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Tidskriftsartikel (refereegranskat)abstract
- Background: Injury by the sting of Lesser weever fish (Trachinus vipera) may lead to severe pain, edema or tissue necrosis. Cellular effects of the venom are still incompletely understood. Previous observations revealed that purified Lesser weever fish venom (LWFV) induces suicidal death of erythrocytes and HCT116 human colon carcinoma cells. The present study addressed the effect of the venom on colon carcinoma cell toxicity, shape and migration both in p53+/+ and/or p53-/- conditions. Methods: Cells were exposed to medium without or with 500 μg/ ml LWFV. Cell shape, cell area and circularity were visualized and quantified by fluorescence microscopy. Cell volume, granularity and cells toxicity were assessed via the apoptotic parameters dissipation of mitochondrial inner transmembrane potential, phosphatidylserine surface exposure and cell membrane permeabilization were measured utilizing flow cytometry. Cell migration was evaluated using wound healing assay and two-dimensional migration assay. Results: LWFV treatment was followed by a marked change of cell shape and size, significant decrease of cell area and circularity, significant impairment of cell migration, as well as induction of apoptosis after long exposition. Conclusions: LWFV exposure leads to cell shrinkage, increased granularity, apoptosis and impairment of cell migration, effects presumably contributing to LWFV-induced tissue injury.
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| 8. |
- Fluckiger, Aurélie, et al.
(författare)
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Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 369:6506, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae. Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2K(b)-restricted CD8(+) T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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| 9. |
- Galluzzi, Lorenzo, et al.
(författare)
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Mitochondrial membrane permeabilization in neuronal injury.
- 2009
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Ingår i: Nature reviews. Neuroscience. - : Springer Science and Business Media LLC. - 1471-0048 .- 1471-003X. ; 10:7, s. 481-94
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Forskningsöversikt (refereegranskat)abstract
- Acute neurological conditions such as cerebrovascular diseases and trauma are associated with irreversible loss of neurons and glial cells. Severe or prolonged injury results in uncontrollable cell death within the core of lesions. Conversely, cells that are less severely damaged succumb in a relatively slow fashion, frequently via the intrinsic pathway of cell death, through the deterioration of mitochondrial functions. The permeabilization of mitochondrial membranes determines whether cells will succumb to or survive the injury, and represents a 'point of no return' in mitochondrial cell death. It is therefore an attractive target for the development of new neuroprotective interventions.
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| 10. |
- Galluzzi, Lorenzo, et al.
(författare)
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Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer
- 2012
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Ingår i: Cell Reports. - Cambridge : Cell press. - 2211-1247. ; 2:2, s. 257-269
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Tidskriftsartikel (refereegranskat)abstract
- Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.
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| 11. |
- Hangen, Emilie, et al.
(författare)
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Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis
- 2015
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Ingår i: Molecular cell. - : Elsevier BV. - 1097-4164 .- 1097-2765. ; 58:6, s. 1001-1014
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF-deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis.
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| 12. |
- Hangen, Emilie, et al.
(författare)
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Life with or without AIF.
- 2010
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Ingår i: Trends in biochemical sciences. - : Elsevier BV. - 0968-0004. ; 35:5, s. 278-87
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Forskningsöversikt (refereegranskat)abstract
- Apoptosis-inducing factor (AIF) was initially discovered as a caspase-independent death effector. AIF fulfills its lethal function after its release from mitochondria and its translocation to the nucleus of the dying cell. The contribution of AIF to programmed cell death is dependent upon the cell type and apoptotic insult. Recent in vivo data indicate that, in addition to its lethal activity, AIF plays a vital mitochondrial role in healthy cells. A segment of AIF which is dispensable for its apoptotic function carries an NADH-oxidase domain that regulates the respiratory chain complex I and is required for cell survival, proliferation and mitochondrial integrity. Mice that express reduced levels of AIF constitute a reliable model of complex I deficiency. Here we discuss recent reports on the survival-related function(s) of AIF.
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| 13. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 14. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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| 15. |
- Li, Hongfu, et al.
(författare)
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Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells.
- 2011
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 31:10, s. 2106-2115
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxic-ischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4±14.6mm(3) in controls (n=15) to 27.6±6.2mm(3) in lithium-treated animals (n=14) 7 weeks after HI (P<0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1β and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival.Journal of Cerebral Blood Flow & Metabolism advance online publication, 18 May 2011; doi:10.1038/jcbfm.2011.75.
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| 16. |
- Meier, Karsten, et al.
(författare)
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The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35
- 2023
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Ingår i: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- The obligate intracellular bacterium Chlamydia trachomatis inserts a family of inclusion membrane (Inc) proteins into the membrane of its vacuole (the inclusion). The Inc CpoS is a critical suppressor of host cellular immune surveillance, but the underlying mechanism remained elusive. By complementing a cpoS mutant with various natural orthologs and variants of CpoS, we linked distinct molecular interactions of CpoS to distinct functions. Unexpectedly, we found CpoS to be essential for the formation of inclusion membrane microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. While the function of CpoS in microdomains was uncoupled from its role in the suppression of host cellular defenses, we found the ability of CpoS to interact with Rab GTPases to be required not only for the manipulation of membrane trafficking, such as to mediate transport of ceramide-derived lipids (sphingolipids) to the inclusion, but also for the inhibition of Stimulator of interferon genes (STING)-dependent type I interferon responses. Indeed, depletion of Rab35 phenocopied the exacerbated interferon responses observed during infection with CpoS-deficient mutants. Overall, our findings highlight the role of Inc-Inc interactions in shaping the inclusion microenvironment and the modulation of membrane trafficking as a pathogenic immune evasion strategy.IMPORTANCE: Chlamydia trachomatis is a prevalent bacterial pathogen that causes blinding ocular scarring and urogenital infections that can lead to infertility and pregnancy complications. Because Chlamydia can only grow within its host cell, boosting the intrinsic defenses of human cells may represent a novel strategy to fight pathogen replication and survival. Hence, CpoS, a Chlamydia protein known to block host cellular defenses, or processes regulated by CpoS, could provide new opportunities for therapeutic intervention. By revealing CpoS as a multifunctional virulence factor and by linking its ability to block host cellular immune signaling to the modulation of membrane trafficking, the present work may provide a foundation for such rationale targeting and advances our understanding of how intracellular bacteria can shape and protect their growth niche.
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| 17. |
- Michels, Judith, et al.
(författare)
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Cisplatin Resistance Associated with PARP Hyperactivation
- 2013
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Ingår i: Cancer Research. - Philadelphia : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 73:7, s. 2271-2280
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Tidskriftsartikel (refereegranskat)abstract
- Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7); 2271-80.
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| 18. |
- Michels, Judith, et al.
(författare)
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MCL-1 dependency of cisplatin-resistant cancer cells
- 2014
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Ingår i: Biochemical Pharmacology. - : Elsevier. - 0006-2952 .- 1356-1839. ; 92:1, s. 55-61
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Tidskriftsartikel (refereegranskat)abstract
- The selection of human cancer cell lines in cis-diamminedichloroplatinum(II) (CDDP, best known as cisplatin) is accompanied by stereotyped alterations that contribute to the acquisition of a CDDP-resistant state. Thus, CDDP resistance often leads to the upregulation of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP1) with the consequent intracellular accumulation of poly (ADP-ribose) (PAR)-modified proteins. Here we report another frequent alteration accompanying CDDP resistance, namely upregulation of the antiapoptotic BCL-2 family protein MCL-1. Six out of 8 CDDP resistant cancer cell lines manifested an increase in MCL-1 protein expression level, while only a minority of cell lines overexpressed BCL-2 or BCL-XL. BCL-XL was decreased in six out of 8 cancer cell lines. Importantly, MCL-1 overexpressing, CDDP resistant cells appear to be 'addicted' to MCL-1 because they died upon depletion of MCL-1 by RNA interference or pharmacological inhibition of MCL-1 expression by the BH3 mimetic obatoclax. Knockdown of PARP1 did not succeed in reducing MCL-1 expression, while depletion or inhibition of MCL-1 failed to affect the activity of PARP1. Hence, the two resistance mechanisms are not linked to each other by a direct cause-effect relationship. Importantly, CDDP-resistant, MCL-1 overexpressing human non-small cell lung cancers responded to monotherapy with obatoclax in vivo, in xenotransplanted mice, underscoring the probable therapeutic relevance of these findings.
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| 19. |
- Ring, Julia, et al.
(författare)
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Mitochondrial energy metabolism is required for lifespan extension by the spastic paraplegia-associated protein spartin
- 2017
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Ingår i: Microbial Cell. - : Shared Science Publishers OG. - 2311-2638. ; 4:12, s. 411-422
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary spastic paraplegias, a group of neurodegenerative disorders, can be caused by loss-of-function mutations in the protein spartin. However, the physiological role of spartin remains largely elusive. Here we show that heterologous expression of human or Drosophila spartin extends chronological lifespan of yeast, reducing age-associated ROS production, apoptosis, and necrosis. We demonstrate that spartin localizes to the proximity of mitochondria and physically interacts with proteins related to mitochondrial and respiratory metabolism. Interestingly, Nde1, the mitochondrial external NADH dehydrogenase, and Pda1, the core enzyme of the pyruvate dehydrogenase complex, are required for spartin-mediated cytoprotection. Furthermore, spartin interacts with the glycolysis enhancer phospo-fructokinase-2,6 (Pfk26) and is sufficient to complement for PFK26-deficiency at least in early aging. We conclude that mitochondria-related energy metabolism is crucial for spartin's vital function during aging and uncover a network of specific interactors required for this function.
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| 20. |
- Rockenfeller, Patrick, et al.
(författare)
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Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast : a model for lipotoxicity
- 2018
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 25:4, s. 765-781
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Tidskriftsartikel (refereegranskat)abstract
- The loss of lipid homeostasis can lead to lipid overload and is associated with a variety of disease states. However, little is known as to how the disruption of lipid regulation or lipid overload affects cell survival. In this study we investigated how excess diacylglycerol (DG), a cardinal metabolite suspected to mediate lipotoxicity, compromises the survival of yeast cells. We reveal that increased DG achieved by either genetic manipulation or pharmacological administration of 1,2-dioctanoyls-n-glycerol (DOG) triggers necrotic cell death. The toxic effects of DG are linked to glucose metabolism and require a functional Rim101 signaling cascade involving the Rim21-dependent sensing complex and the activation of a calpain-like protease. The Rim101 cascade is an established pathway that triggers a transcriptional response to alkaline or lipid stress. We propose that the Rim101 pathway senses DG-induced lipid perturbation and conducts a signaling response that either facilitates cellular adaptation or triggers lipotoxic cell death. Using established models of lipotoxicity, i.e., high-fat diet in Drosophila and palmitic acid administration in cultured human endothelial cells, we present evidence that the core mechanism underlying this calpain-dependent lipotoxic cell death pathway is phylogenetically conserved.
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| 21. |
- Rodriguez, Juan, 1983, et al.
(författare)
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Lack of the brain-specific isoform of apoptosis-inducing factor aggravates cerebral damage in a model of neonatal hypoxia-ischemia.
- 2018
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Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis-inducing factor (AIF) may contribute to neuronal cell death, and its influence is particularly prominent in the immature brain after hypoxia-ischemia (HI). A brain-specific AIF splice-isoform (AIF2) has recently been discovered, but has not yet been characterized at the genetic level. The aim of this study was to determine the functional and regulatory profile of AIF2 under physiological conditions and after HI in mice. We generated AIF2 knockout (KO) mice by removing the AIF2-specific exon and found that the relative expression of Aif1 mRNA increased in Aif2 KO mice and that this increase became even more pronounced as Aif2 KO mice aged compared to their wild-type (WT) littermates. Mitochondrial morphology and function, reproductive function, and behavior showed no differences between WT and Aif2 KO mice. However, lack of AIF2 enhanced brain injury in neonatal mice after HI compared to WT controls, and this effect was linked to increased oxidative stress but not to caspase-dependent or -independent apoptosis pathways. These results indicate that AIF2 deficiency exacerbates free radical production and HI-induced neonatal brain injury.
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| 22. |
- Sixt, Barbara Susanne, et al.
(författare)
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Chlamydia trachomatis fails to protect its growth niche against pro-apoptotic insults
- 2019
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Ingår i: Cell Death and Differentiation. - : Nature Publishing Group. - 1350-9047 .- 1476-5403. ; 26:8, s. 1485-1500
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Tidskriftsartikel (refereegranskat)abstract
- Chlamydia trachomatis is an obligate intracellular bacterial agent responsible for ocular infections and sexually transmitted diseases. It has been postulated that Chlamydia inhibits apoptosis in host cells to maintain an intact replicative niche until sufficient infectious progeny can be generated. Here we report that, while cells infected with C. trachomatis are protected from apoptosis at early and mid-stages of infection, they remain susceptible to the induction of other cell death modalities. By monitoring the fate of infected cells by time-lapse video microscopy and by analyzing host plasma membrane integrity and the activity of caspases, we determined that C. trachomatis-infected cells exposed to pro-apoptotic stimuli predominately died by a mechanism resembling necrosis. This necrotic death of infected cells occurred with kinetics similar to the induction of apoptosis in uninfected cells, indicating that C. trachomatis fails to considerably prolong the lifespan of its host cell when exposed to pro-apoptotic insults. Inhibitors of bacterial protein synthesis partially blocked necrotic death of infected cells, suggesting that the switch from apoptosis to necrosis relies on an active contribution of the bacteria. Tumor necrosis factor alpha (TNF-α)-mediated induction of necrosis in cells infected with C. trachomatis was not dependent on canonical regulators of necroptosis, such as RIPK1, RIPK3, or MLKL, yet was blocked by inhibition or depletion of CASP8. These results suggest that alternative signaling pathways regulate necrotic death in the context of C. trachomatis infections. Finally, consistent with the inability of C. trachomatis to preserve host cell viability, necrosis resulting from pro-apoptotic conditions significantly impaired production of infectious progeny. Taken together, our findings suggest that Chlamydia's anti-apoptotic activities are not sufficient to protect the pathogen's replicative niche.
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| 23. |
- Sixt, Barbara Susanne, et al.
(författare)
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Chlamydia trachomatis' struggle to keep its host alive
- 2017
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Ingår i: Microbial cell (Graz, Austria). - : Shared Science Publishers OG. - 2311-2638. ; 4:3, s. 101-104
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Tidskriftsartikel (refereegranskat)abstract
- Bacteria of the phylum Chlamydiae infect a diverse range of eukaryotic host species, including vertebrate animals, invertebrates, and even protozoa. Characteristics shared by all Chlamydiae include their obligate intracellular lifestyle and a biphasic developmental cycle. The infectious form, the elementary body (EB), invades a host cell and differentiates into the replicative form, the reticulate body (RB), which proliferates within a membrane-bound compartment, the inclusion. After several rounds of division, RBs retro-differentiate into EBs that are then released to infect neighboring cells. The consequence of this obligatory transition between replicative and infectious forms inside cells is that Chlamydiae absolutely depend on the viability and functionality of their host cell throughout the entire infection cycle. We recently conducted a forward genetic screen in Chlamydia trachomatis, a common sexually transmitted human pathogen, and identified a mutant that caused premature death in the majority of infected host cells. We employed emerging genetic tools in Chlamydia to link this cytotoxicity to the loss of the protein CpoS (Chlamydia promoter of survival) that normally localizes to the membrane of the pathogen-containing vacuole. CpoS-deficient bacteria also induced an exaggerated type-1 interferon response in infected cells, produced reduced numbers of infectious EBs in cell culture, and were cleared faster from the mouse genital tract in a transcervical infection model in vivo. The analysis of this CpoS-deficient mutant yielded unique insights into the nature of cell-autonomous defense responses against Chlamydia and highlighted the importance of Chlamydia-mediated control of host cell fate for the success of the pathogen.
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- Sixt, Barbara Susanne, et al.
(författare)
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The Chlamydia trachomatis Inclusion Membrane Protein CpoS Counteracts STING-Mediated Cellular Surveillance and Suicide Programs
- 2017
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 21:1, s. 113-121
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Tidskriftsartikel (refereegranskat)abstract
- Evading cell death is critical for Chlamydia to maintain a replicative niche, but the underlying mechanisms are unknown. We screened a library of Chlamydia mutants for modulators of cell death. Inactivation of the inclusion membrane protein CpoS (Chlamydia promoter of survival) induced rapid apoptotic and necrotic death in infected cells. The protection afforded by CpoS is limited to the inclusion in which it resides, indicating that it counteracts a spatially restricted pro-death signal. CpoS-deficient Chlamydia induced an exacerbated type I interferon response that required the host cGAS/STING/TBK1/IRF3 signaling pathway. Disruption of STING, but not cGAS or IRF3, attenuated cell death, suggesting that STING mediates Chlamydia-induced cell death independent of its role in regulating interferon responses. CpoS-deficient strains are attenuated in their ability to propagate in cell culture and are cleared faster from the murine genital tract, highlighting the importance of CpoS for Chlamydia pathogenesis.
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- Tasdemir, Ezgi, et al.
(författare)
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Regulation of autophagy by cytoplasmic p53.
- 2008
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Ingår i: Nature cell biology. - : Springer Science and Business Media LLC. - 1476-4679 .- 1465-7392. ; 10:6, s. 676-87
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Tidskriftsartikel (refereegranskat)abstract
- Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.
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