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  • 1.
    Andersson, Eva
    et al.
    Linköping University, Department of Biomedicine and Surgery, Dermatology. Linköping University, Faculty of Health Sciences.
    Björklind, Carina
    Linköping University, Department of Biomedicine and Surgery, Dermatology. Linköping University, Faculty of Health Sciences.
    Törma, Hans
    Department of Dermatology, University Hospital, Uppsala, Sweden.
    Vahlquist, Anders
    Linköping University, Department of Biomedicine and Surgery, Dermatology. Linköping University, Faculty of Health Sciences.
    The metabolism of vitamin A to 3,4-didehydroretinol can be demonstrated in human keratinocytes, melanoma cells and HeLa cells, and is correlated to cellular retinoid-binding protein expression1994In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1224, no 3, p. 349-354Article in journal (Refereed)
    Abstract [en]

    Conversion of retinol to 3,4-didehydroretinol is probably a rate-limiting step in the formation of 3,4-didehydroretinoic acid, a candidate ligand for nuclear retinoid receptors in human epidermal keratinocytes. To investigate whether this metabolic pathway also exists in other cell systems, we compared the retinoid concentrations and the bioconversion of [3H]retinol to [3H]3,4-didehydroretinol in human primary keratinocytes, human cervical carcinoma (HeLa) cells, human melanoma (JKM86-4) cells, monkey kidney epithelium (CV-1) cells, and murine teratocarcinoma (F9) cells. The cellular retinol concentration ranged from 2.33 to 99.1 pmol/mg protein with the highest values observed in keratinocytes. 3,4-Didehydroretinol was only detected in cells of human origin and its concentration ranged from 0.24 pmol/mg in HeLa to 34.6 pmol/mg in the keratinocytes. Incubation with [3H]retinol for 1–24 h resulted in a rapid appearance of [3H]3,4-didehydroretinol in human keratinocytes, and to a lesser extent in HeLa and melanoma cells, but not in the other cells. Analysis of cellular retinol- and retinoic acid-binding protein concentrations showed a correlation to the cells' ability to accumulate 3,4-didehydroretinol, suggesting a role for these proteins in the 3,4-didehydro metabolic pathway. The combined results suggest that although 3,4-didehydroretinol is most typical for human keratinocytes, studies of its metabolism are also feasible in HeLa cells which contain low levels of retinoid-binding proteins.

  • 2.
    Baxtera, Shannon A.
    et al.
    University of Manitoba, Winnipeg, Canada.
    Cheung, David Y.
    University of Manitoba, Winnipeg, Canada.
    Bocangel, Patricia
    University of Manitoba, Winnipeg, Canada.
    Kim, Hae K.
    University of Manitoba, Winnipeg, Canada.
    Herbert, Krista
    University of Manitoba, Winnipeg, Canada.
    Douville, Josette M.
    University of Manitoba, Winnipeg, Canada.
    Jangamreddy, Jaganmohan Reddy
    University of Manitoba, Winnipeg, Canada.
    Zhang, Shunzhen
    University of Manitoba, Winnipeg, Canada.
    Eisensta, David D.
    University of Manitoba, Winnipeg, Canada.
    Wigle, Jeffrey T.
    University of Manitoba, Winnipeg, Canada.
    Regulation of the lymphatic endothelial cell cycle by the PROX1 homeodomain protein2011In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1813, no 1, p. 201-212Article in journal (Refereed)
    Abstract [en]

    The homeobox transcription factor PROX1 is essential for the development and maintenance of lymphatic vasculature. How PROX1 regulates lymphatic endothelial cell fate remains undefined. PROX1 has been shown to upregulate the expression of Cyclin E, which mediates the G1 to S transition of the cell cycle. Here we demonstrate that PROX1 activates the mouse Cyclin E1 (Ccne1) promoter via two proximal E2F-binding sites. We have determined that the N-terminal region of PROX1 is sufficient to activate a 1-kb Ccne1 promoter, whereas the homeodomain is dispensable for activation. We have identified that the Prospero domain 1 (PD1) is required for the nuclear localization of PROX1. Our comparison of two DNA-binding-deficient constructs of PROX1 showed a cell-type-specific difference between these two proteins in both their localization and function. We demonstrated that siRNA-mediated knockdown of PROX1 in lymphatic endothelial cells decreases progression from G1 to S phase of the cell cycle. We conclude that PROX1 activates the Ccne1 promoter independent of DNA binding, and our results illustrate a novel role for PROX1 in the regulation of lymphatic endothelial cell proliferation.

  • 3.
    Ghavami, Saeid
    et al.
    Department of Physiology, University of Manitoba, Canada.
    Cunnington, Ryan H
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Yeganeh, Behzad
    Department of Physiology, University of Manitoba, Canada.
    Davies, Jared J L
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Rattan, Sunil G
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Bathe, Krista
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Kavosh, Morvarid
    Institute of Cardiovascular Sciences, University of Manitoba, Canada.
    Los, Marek J
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Freed, Darren H
    Department of Physiology, University of Manitoba, Canada.
    Klonisch, Thomas
    Department of Human Anatomy and Cell Science, University of Manitoba, Canada.
    Pierce, Grant N
    Department of Physiology, University of Manitoba, Canada.
    Halayko, Andrew J
    Department of Physiology, University of Manitoba, Canada.
    Dixon, Ian M C
    Department of Physiology, University of Manitoba, Canada.
    Autophagy regulates trans fatty acid-mediated apoptosis in primary cardiac myofibroblasts.2012In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1823, no 12, p. 2274-2286Article in journal (Refereed)
    Abstract [en]

    Trans fats are not a homogeneous group of molecules and less is known about the cellular effects of individual members of the group. Vaccenic acid (VA) and elaidic acid (EA) are the predominant trans monoenes in ruminant fats and vegetable oil, respectively. Here, we investigated the mechanism of cell death induced by VA and EA on primary rat ventricular myofibroblasts (rVF). The MTT assay demonstrated that both VA and EA (200μM, 0-72h) reduced cell viability in rVF (P<0.001). The FACS assay confirmed that both VA and EA induced apoptosis in rVF, and this was concomitant with elevation in cleaved caspase-9, -3 and -7, but not caspase-8. VA and EA decreased the expression ratio of Bcl2:Bax, induced Bax translocation to mitochondria and decrease in mitochondrial membrane potential (Δψ). BAX and BAX/BAK silencing in mouse embryonic fibroblasts (MEF) inhibited VA and EA-induced cell death compared to the corresponding wild type cells. Transmission electron microscopy revealed that VA and EA also induced macroautophagosome formation in rVF, and immunoblot analysis confirmed the induction of several autophagy markers: LC3-β lipidation, Atg5-12 accumulation, and increased beclin-1. Finally, deletion of autophagy genes, ATG3 and ATG5 significantly inhibited VA and EA-induced cell death (P<0.001). Our findings show for the first time that trans fat acid (TFA) induces simultaneous apoptosis and autophagy in rVF. Furthermore, TFA-induced autophagy is required for this pro-apoptotic effect. Further studies to address the effect of TFA on the heart may reveal significant translational value for prevention of TFA-linked heart disease.

  • 4.
    Ghavami, Saeid
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Kadkhoda, Kamran
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Mutawe, Mark M.
    Department of Physiology, University of Manitoba, Canada; Manitoba Institute of Child's Health, University of Manitoba, Canada.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Bay, Graham H.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, University of Manitoba, Canada.
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
    Halayko, Andrew J.
    Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada; Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada .
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Role of BNIP3 in TNF-induced cell death - TNF upregulates BNIP3 expression2009In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1793, no 3, p. 546-560Article in journal (Refereed)
    Abstract [en]

    Tumor necrosis factor alpha (TNF) is a cytokine that induces caspase-dependent (apoptotic) and caspase-independent (necrosis-like) cell death in different cells. We used the murine fibrosarcoma cell line model L929 and a stable L929 transfectant over-expressing a mutated dominant-negative form of BNIP3 lacking the C-terminal transmembrane (TM) domain (L929-ΔTM-BNIP3) to test if TNF-induced cell death involved pro-apoptotic Bcl2 protein BNIP3. Treatment of cells with TNF in the absence of actinomycin D caused a rapid fall in the mitochondrial membrane potential (ΔΨm) and a prompt increase in reactive oxygen species (ROS) production, which was significantly less pronounced in L929-ΔTM-BNIP3. TNF did not cause the mitochondrial release of apoptosis inducing factor (AIF) and Endonuclease G (Endo-G) but provoked the release of cytochrome c, Smac/Diablo, and Omi/HtrA2 at similar levels in both L929 and in L929-ΔTM-BNIP3 cells. We observed TNF-associated increase in the expression of BNIP3 in L929 that was mediated by nitric oxide and significantly inhibited by nitric oxide synthase inhibitor N5-(methylamidino)-l-ornithine acetate. In L929, lysosomal swelling and activation were markedly increased as compared to L929-ΔTM-BNIP3 and could be inhibited by treatment with inhibitors to vacuolar H+-ATPase and cathepsins −B/−L. Together, these data indicate that TNF-induced cell death involves BNIP3, ROS production, and activation of the lysosomal death pathway.

  • 5.
    Ghavami, Saeid
    et al.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Kerkhoff, Claus
    Institute of Experimental Dermatology, Münster, Germany.
    Chazin, Walter J.
    Department of Biochemistry Vanderbilt University, Nashville, USA; Department of Chemistry, Vanderbilt University, Nashville, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232-8725, USA.
    Kadhoka, Kamran
    Manitoba Institute of Cell Biology, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.
    Xiao, Wenyan
    Manitoba Institute of Cell Biology, Canada.
    Zusea, Anne
    Manitoba Institute of Cell Biology, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.
    Hashemi, Mohammad
    Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Science, Zahedan, Iran.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology, Canada b Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.
    Schulze-Osthoff, Klaus
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada; BioApplications Enterprises, Winnipeg, MB, Canada.
    S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA22008In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1783, no 2, p. 297-311Article in journal (Refereed)
    Abstract [en]

    A complex of two S100 EF-hand calcium-binding proteins S100A8/A9 induces apoptosis in various cells, especially tumor cells. Using several cell lines, we have shown that S100A8/A9-induced cell death is not mediated by the receptor for advanced glycation endproducts (RAGE), a receptor previously demonstrated to engage S100 proteins. Investigation of cell lines either deficient in, or over-expressing components of the death signaling machinery provided insight into the S100A8/A9-mediated cell death pathway. Treatment of cells with S100A8/A9 caused a rapid decrease in the mitochondrial membrane potential (ΔΨm) and activated Bak, but did not cause release of apoptosis-inducing factor (AIF), endonuclease G (Endo G) or cytochrome c. However, both Smac/DIABLO and Omi/HtrA2 were selectively released into the cytoplasm concomitantly with a decrease in Drp1 expression, which inhibits mitochondrial fission machinery. S100A8/A9 treatment also resulted in decreased expression of the anti-apoptotic proteins Bcl2 and Bcl-XL, whereas expression of the pro-apoptotic proteins Bax, Bad and BNIP3 was not altered. Over-expression of Bcl2 partially reversed the cytotoxicity of S100A8/A9. Together, these data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins.

  • 6.
    Ghavami, Saeid
    et al.
    University of Manitoba, Canada.
    Sharma, Pawan
    University of Manitoba, Canada.
    Yeganeh, Behzad
    University of Manitoba, Canada.
    Ojo, Oluwaseun O.
    University of Manitoba, Canada.
    Jha, Aruni
    University of Manitoba, Canada.
    Mutawe, Mark M.
    University of Manitoba, Canada.
    Kashani, Hessam H.
    University of Manitoba, Canada.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Klonisch, Thomas
    University of Manitoba, Canada .
    Unruh, Helmut
    University of Manitoba, Canada .
    Halayko, Andrew J.
    University of Manitoba, Canada.
    Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins2014In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1843, no 7, p. 1259-1271Article in journal (Refereed)
    Abstract [en]

    HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1 alpha) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX(-/-)/BAIC(-/) murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease.

  • 7.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada.
    Grabarek, Jerzy
    Pomeranian Medical University, Szczecin, Poland.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Wiechec, Emilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences.
    Fredriksson, Bengt-Arne
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rao, Rama K.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Cieślar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences.
    Panigrahi, Soumya
    Lerner Research Institute, Cleveland, OH, USA.
    Łos, Marek
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences.
    Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells2013In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1833, no 9, p. 2057-2069Article in journal (Refereed)
    Abstract [en]

    The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca2 +, cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/β-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, breast cancer cells, and to lesser degree in human normal dermal fibroblasts. Interestingly, autophagy induced by Salinomycin is a cell protective mechanism in all tested cancer cell lines. Furthermore, Salinomycin induces mitophagy, mitoptosis and increased mitochondrial membrane potential (∆Ψ) in a subpopulation of cells. Salinomycin strongly, and in time-dependent manner decreases cellular ATP level. Contrastingly, human normal dermal fibroblasts treated with Salinomycin show some initial decrease in mitochondrial mass, however they are largely resistant to Salinomycin-triggered ATP-depletion. Our data provide new insight into the molecular mechanism of preferential toxicity of Salinomycin towards cancer cells, and suggest possible clinical application of Salinomycin in combination with autophagy inhibitors (i.e. clinically-used Chloroquine). Furthermore, we discuss preferential Salinomycins toxicity in the context of Warburg effect.

  • 8.
    Lindmark, Maria
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Karlsson, Anna
    The Phagocyte Laboratory, Department of Medical Microbiology, Göteborg University, Göteborg, Sweden.
    Serrander, Lena
    Division of Infectious Diseases, University Hospital Geneva, Geneva, Switzerland.
    Francois, Patrice
    Division of Infectious Diseases, University Hospital Geneva, Geneva, Switzerland.
    Lew, Daniel
    Division of Infectious Diseases, University Hospital Geneva, Geneva, Switzerland.
    Rasmusson, Birgitta
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nüße, Oliver
    Immunology Group, Faculty of Science, Univ. Nancy, Vandoeuvre, France.
    Synaptotagmin II could confer Ca2+ sensitivity to phagocytosis in human neutrophils2002In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1590, no 1-3, p. 159-166Article in journal (Refereed)
    Abstract [en]

    Phagolysosome fusion and granule exocytosis in neutrophils are calcium-dependent processes. The calcium requirements vary between granule types, suggesting the presence of different calcium sensors. The synaptotagmins, a family of calcium-binding proteins, previously shown to participate in vesicle fusion and vesicle recycling in excitable cells, are putative calcium-sensors of exocytosis in excitable cells. In this study, we show that synaptotagmin II is present in human neutrophils and may participate in phagocytic and in exocytotic processes. In protein extracts from human neutrophils, we identified synaptotagmin II by Western blot as an 80 kDa protein. Subcellular fractionation revealed that synaptotagmin II was associated with the specific granules. In fMLP-stimulated cells, synaptotagmin II translocated to the plasma membrane. This correlated with the upregulation of complement receptor 3 (CR 3), reflecting the translocation of specific granules to the cell surface. Synaptotagmin II also translocated to the phagosome after complement-mediated phagocytosis in the presence of calcium. LAMP-1 translocated in parallel but probably was located to another subcellular compartment than synaptotagmin II. Under calcium-reduced conditions, neither synaptotagmin II nor LAMP-1 translocated to the phagosome. We therefore suggest a role for synaptotagmin II as calcium-sensor during phagocytosis and secretion in neutrophils.

  • 9.
    Los, Marek Jan
    et al.
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Panigrahi, Soumya
    Department of Immunology, Lerner Research Institute, Cleveland, USA.
    Rashedi, Iran
    Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.
    Mandal, Sanat
    Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
    Stetefeld, Joerg
    Department of Chemistry, University of Manitoba, Winnipeg, Canada.
    Essmann, Frank
    Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
    Schulze-Osthoff, Klaus
    Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
    Apoptin, a tumor-selective killer2009In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1793, no 8, p. 1335-1342Article, review/survey (Refereed)
    Abstract [en]

    Apoptin, a small protein from chicken anemia virus, has attracted great attention, because it specifically kills tumor cells while leaving normal cells unharmed. The subcellular localization of apoptin appears to be crucial for this tumor-selective activity. In normal cells, apoptin resides in the cytoplasm, whereas in cancerous cells it translocates into the nucleus. The nuclear translocation of apoptin is largely controlled by its phosphorylation. In tumor cells, apoptin causes the nuclear accumulation of survival kinases including Akt and is phosphorylated by CDK2. Thereby, apoptin redirects survival signals into cell death responses. Apoptin also binds as a multimeric complex to DNA and interacts with several nuclear targets, such as the anaphase-promoting complex, resulting in a G2/M phase arrest. The proapoptotic signal of apoptin is then transduced from the nucleus to cytoplasm by Nur77, which triggers a p53-independent mitochondrial death pathway. In this review, we summarize recent discoveries of apoptin's mechanism of action that might provide intriguing insights for the development of novel tumor-selective anticancer drugs.

  • 10.
    Lundqvist, Helen
    et al.
    Phagocyte Research Laboratory, Department of Medical Microbiology and Immunology, University of Göteborg, Göteborg, Sweden.
    Gustafsson, Mikael
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Johansson, Agneta
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Särndahl, Eva
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Dahlgren, Claes
    Phagocyte Research Laboratory, Department of Medical Microbiology and Immunology, University of Göteborg, Göteborg, Sweden.
    Neutrophil control of formylmethionyl-leucyl-phenylalanine induced mobilization of secretory vesicles and NADPH-oxidase activation: Effect of an association of the ligand-receptor complex to the cytoskeleton1994In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1224, no 1, p. 43-50Article in journal (Refereed)
    Abstract [en]

    The stimulus formylmethionyl-leucyl-phenylalanine (FMLP) interacts with neutrophils and generates signal(s) in the cells that induces mobilization of the secretory vesicles as well as activation of the superoxide anion/hydrogen peroxide generating NADPH-oxidase. Binding, at 15°C, of FMLP to its neutrophil surface receptor is followed by an association of the ligand-receptor complex to the cell cytoskeleton, and this association occurs concomitant with a desensitization of the cells with respect to activation of the NADPH-oxidase. Other stimuli can still activate the oxidase (in fact even induce a primed response), indicating that the observed phenomenon is stimulus specific and could not be accounted for by an effect on the oxidase itself, but rather that the association of the ligand-receptor complex to the cytoskeleton eliminates the capacity of the complex to generate the signal(s) that activates the NADPH-oxidase. The cytoskeleton associated ligand-receptor complex generates, however, the signal(s) responsible for mobilization of the secretory vesicles, to the plasma membrane, and this mobilization occurs without any increase in the intracellular concentration of free Ca2+.

  • 11.
    Löfgren, Ragnhild
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Serrander, Lena
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Forsberg, Maria
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Wilsson, Åsa
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Wasteson, Åke
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    CR3, FcγRIIA and FcγRIIIB induce activation of the respiratory burst in human neutrophils: the role of intracellular Ca2+, phospholipase D and tyrosine phosphorylation1999In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1452, no 1, p. 46-59Article in journal (Refereed)
    Abstract [en]

    Human neutrophils express two different types of phagocytic receptors, complement receptors (CR) and Fc receptors. In order to characterize the different signaling properties of each receptor we have used non-adherent human neutrophils and investigated CR3, FcγRIIA and FcγRIIIB for their signaling capacity. Selective activation of each receptor was achieved by coupling specific antibodies to heat-killed Staphylococcus aureus particles, Pansorbins, through their Fc moiety. Despite the fact that these particles are not phagocytosed, we show that addition of Pansorbins with anti-CD18 antibodies recognizing CR3 induced prominent signals leading to a respiratory burst. Stimulation with anti-FcγRIIIB Pansorbins induced about half of the response induced by anti-CR3 Pansorbins, whereas anti-FcγRIIA Pansorbins induced an even weaker signal. However, FcγRIIA induced strong phosphorylation of p72syk whereas FcγRIIIB induced only a very weak p72syk phosphorylation. During CR3 stimulation no tyrosine phosphorylation of p72syk was seen. Both phospholipase D and NADPH oxidase activities were dependent on intracellular calcium. This is in contrast to tyrosine phosphorylation of p72syk that occurred even in calcium-depleted cells, indicating that oxygen metabolism does not affect p72syk phosphorylation. Inhibitors of tyrosine phosphorylation blocked the respiratory burst induced by both FcγRIIA and FcγRIIIB as well as CR3. This shows that tyrosine phosphorylation of p72syk is an early signal in the cascade induced by FcγRIIA but not by CR3.

  • 12.
    Reddy Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Panigrahi, Soumya
    Department of Medicine/Infectious Diseases, Case Western Reserve University, Cleveland, USA.
    Los, Marek J.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Poland.
    Monitoring of autophagy is complicated: Salinomycin as an example2015In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, ISSN 0167-4889, Vol. 1853, no 3, p. 604-610Article in journal (Refereed)
    Abstract [en]

    Monitoring of autophagy is challenging because of its multiple steps and lack of single befitting technique for a complete mechanistic understanding, which makes the task complicated. Here, we evaluate the functionality of autophagy triggered by salinomycin (anti-cancer stem cell agent) using flow cytometry and advanced microscopy. We show that salinomycin does induce functional autophagy at lower concentrations and such a dose is cell type-dependent. For example, PC3 cells show active autophagic flux at 10μM concentration of salinomycin while murine embryonic fibroblasts already show an inhibition of flux at such doses. A higher concentration of salinomycin (i.e. 30μM) inhibits autophagic flux in both cell types. The data confirms our previous findings that salinomycin is an inducer of autophagy, whereas autophagic flux inhibition is a secondary response.

  • 13.
    Serrander, Lena
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Larsson, Jenny
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Lundqvist, Helen
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Lindmark, Maria
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Fällman, Maria
    Department of Medical Microbiology, University of Umeå, Umeå, Sweden.
    Dahlgren, Claes
    Department of Medical Microbiology, University of Göteborg, Göteborg, Sweden.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Particles binding β2-integrins mediate intracellular production of oxidative metabolites in human neutrophils independently of phagocytosis1999In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1452, no 2, p. 133-144Article in journal (Refereed)
    Abstract [en]

    Complement-opsonised particles are readily ingested by human neutrophils through a complement receptor-mediated process leading to phagolysosome fusion and production of oxidative metabolites. To investigate the complement receptor 3 (CR3)-associated signal system involved, cells were challenged with protein A-positive, heat-killed Staphylococcus aureus to which antibodies with specificity for the subunits of the β2-integrins, i.e. anti-CD11b (the α subunit of CR3) and anti-CD18 (the β subunit of CR3), were bound through their Fc moiety. Despite not being ingested by the neutrophils, the surface associated anti-CD18- and anti-CD11b-coated particles were able to activate the neutrophil NADPH-oxidase. Also anti-CD11a- (the α subunit of LFA-1) and to a lesser extent anti-CD11c- (the α subunit of CR4) coated particles were able to trigger the NADPH-oxidase. The NADPH-oxidase was activated without extracellular release of reactive oxygen species. The activity was inhibited by cytochalasin B, suggesting a necessary role for the cytoskeleton in the signalling pathway that activates the oxidase. We show that particle-mediated cross-linking of β2-integrins on the neutrophil surface initiates a signalling cascade, involving cytoskeletal rearrangements, leading to an activation of the NADPH-oxidase without phagosome formation or extracellular release of reactive oxygen species.

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