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  • 1.
    Blixt, Martin K. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Shirazi Fard, Shahrzad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    All-Ericsson, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Adding another piece to the retinoblastoma puzzle2015In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 6, article id e1957Article in journal (Refereed)
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  • 2.
    Cancer, Matko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Drews, Lisa F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bolin, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Rosén, Gabriela
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nelander, Sven
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Forsberg Nilsson, Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weishaupt, Holger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Johansson, Fredrik K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells2019In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 10, article id 881Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.

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  • 3.
    Dadras, Mahsa Shahidi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Weill Cornell Med, Brain & Mind Res Inst, New York, NY 10021 USA..
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mezheyeuski, Artur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liu, Sijia
    Leiden Univ, Oncode Inst, Dept Cell & Chem Biol, Med Ctr, Leiden, Netherlands..
    Gelabert, Caroline
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gomez-Puerto, Maria Catalina
    Leiden Univ, Oncode Inst, Dept Cell & Chem Biol, Med Ctr, Leiden, Netherlands..
    Gallini, Radiosa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    ten Dijke, Peter
    Leiden Univ, Oncode Inst, Dept Cell & Chem Biol, Med Ctr, Leiden, Netherlands..
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma2021In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 12, no 10, article id 932Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, regulate asymmetric cell division of neuro-glial progenitors and neurite motility. We, therefore, studied the role of the Par3 protein (encoded by PARD3) in GBM. GBM patient transcriptomic data and patient-derived culture analysis indicated diverse levels of expression of PARD3 across and independent from subtypes. Multiplex immunolocalization in GBM tumors identified Par3 protein enrichment in SOX2-, CD133-, and NESTIN-positive (stem-like) cells. Analysis of GBM cultures of the three subtypes (proneural, classical, mesenchymal), revealed decreased gliomasphere forming capacity and enhanced invasiveness upon silencing Par3. GBM cultures with suppressed Par3 showed low expression of stemness (SOX2 and NESTIN) but higher expression of differentiation (GFAP) genes. Moreover, Par3 silencing reduced the expression of a set of genes encoding mitochondrial enzymes that generate ATP. Accordingly, silencing Par3 reduced ATP production and concomitantly increased reactive oxygen species. The latter was required for the enhanced migration observed upon silencing of Par3 as anti-oxidants blocked the enhanced migration. These findings support the notion that Par3 exerts homeostatic redox control, which could limit the tumor cell-derived pool of oxygen radicals, and thereby the tumorigenicity of GBM.

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  • 4.
    Damhofer, Helene
    et al.
    Inst Canc Res, Div Canc Biol, London, England.;Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Tatar, Tülin
    Inst Canc Res, Div Canc Biol, London, England.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Southgate, Benjamin
    Univ Edinburgh, Ctr Regenerat Med, Edinburgh, Scotland..
    Scarneo, Scott
    Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA.;EydisBio Inc, Durham, NC USA..
    Agger, Karl
    Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Shlyueva, Daria
    Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Morrison, Gillian M.
    Univ Edinburgh, Ctr Regenerat Med, Edinburgh, Scotland..
    Hughes, Philip F.
    Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA.;EydisBio Inc, Durham, NC USA..
    Haystead, Timothy
    Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA.;EydisBio Inc, Durham, NC USA..
    Pollard, Steven M.
    Univ Edinburgh, Ctr Regenerat Med, Edinburgh, Scotland..
    Helin, Kristian
    Inst Canc Res, Div Canc Biol, London, England.;Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers2024In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 15, article id 273Article in journal (Refereed)
    Abstract [en]

    Poor survival and lack of treatment response in glioblastoma (GBM) is attributed to the persistence of glioma stem cells (GSCs). To identify novel therapeutic approaches, we performed CRISPR/Cas9 knockout screens and discovered TGFβ activated kinase (TAK1) as a selective survival factor in a significant fraction of GSCs. Loss of TAK1 kinase activity results in RIPK1-dependent apoptosis via Caspase-8/FADD complex activation, dependent on autocrine TNFα ligand production and constitutive TNFR signaling. We identify a transcriptional signature associated with immune activation and the mesenchymal GBM subtype to be a characteristic of cancer cells sensitive to TAK1 perturbation and employ this signature to accurately predict sensitivity to the TAK1 kinase inhibitor HS-276. In addition, exposure to pro-inflammatory cytokines IFN gamma and TNFα can sensitize resistant GSCs to TAK1 inhibition. Our findings reveal dependency on TAK1 kinase activity as a novel vulnerability in immune-activated cancers, including mesenchymal GBMs that can be exploited therapeutically.

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  • 5.
    Gonzalez-Rodriguez, Patricia
    et al.
    Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    Engskog-Vlachos, Pinelopi
    Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    Zhang, Hanzhao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Hallböök: Stem cells, Retinal Development and Regeneration. Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    Murgoci, Adriana-Natalia
    Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    Zerdes, Ioannis
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden.
    Joseph, Bertrand
    Karolinska Inst, Inst Environm Med, Toxicol Unit, S-17177 Stockholm, Sweden.
    SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG122020In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 11, article id 69Article in journal (Refereed)
    Abstract [en]

    Inactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC). SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values. Targeting autophagy, a conserved catabolic process with critical functions in maintenance of cellular homeostasis and cell conservation under stress condition, is emerging as a potential therapeutic strategy to combat ccRCC. Epigenetics-based pathways are now appreciated as key components in the regulation of autophagy. However, whether loss of function in the SETD2 histone modifying enzyme occurring in ccRCC cells may impact on their ability to undergo autophagy remained to be explored. Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12-containing complex, distinct from the ATG5-ATG12 complex. Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process. Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells. The defect in the ATG12-dependent conjugation system was found to be associated with a decrease autophagic flux, in accord with the role for this ubiquitin-like protein conjugation system in autophagosome formation and expansion. Finally, we report that SETD2 and ATG12 gene expression levels are associated with favorable respective unfavorable prognosis in ccRCC patients. Collectively, our findings bring further argument for considering the SETD2 gene status of ccRCC tumors, when therapeutic interventions, such as targeting the autophagic process, are considered to combat these kidney cancers.

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  • 6.
    Jakic, Bojana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Med Univ Innsbruck, Inst Pharmacol & Genet, Translat Cell Genet, Innsbruck, Austria..
    Olson, William J.
    Med Univ Innsbruck, Inst Pharmacol & Genet, Translat Cell Genet, Innsbruck, Austria.;Univ Innsbruck, Inst Biomed Aging Res, Innsbruck, Austria..
    Siegmund, Kerstin
    Med Univ Innsbruck, Inst Pharmacol & Genet, Translat Cell Genet, Innsbruck, Austria..
    Klepsch, Victoria
    Med Univ Innsbruck, Inst Pharmacol & Genet, Translat Cell Genet, Innsbruck, Austria..
    Kimpel, Janine
    Med Univ Innsbruck, Inst Virol, Innsbruck, Austria..
    Labi, Verena
    Med Univ Innsbruck, Bioctr, Inst Dev Immunol, Innsbruck, Austria..
    Zehn, Dietmar
    Tech Univ Munich, Sch Life Sci Weihenstephan, Div Anim Physiol & Immunol, Freising Weihenstephan, Germany..
    Baier, Gottfried
    Med Univ Innsbruck, Inst Pharmacol & Genet, Translat Cell Genet, Innsbruck, Austria..
    Hermann-Kleiter, Natascha
    Med Univ Innsbruck, Inst Pharmacol & Genet, Translat Cell Genet, Innsbruck, Austria..
    Loss of the orphan nuclear receptor NR2F6 enhances CD8(+) T-cell memory via IFN-gamma2021In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 12, article id 187Article in journal (Refereed)
    Abstract [en]

    Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127(-)KLRG1(+)) or memory precursors cells (MPECs, CD127(+)KLRG1(-)) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we show that loss of the nuclear orphan receptor NR2F6 in germ-line Nr2f6-deficient mice enhances antigen-specific CD8(+) memory formation up to 70 days after bacterial infection with Listeria monocytogenes (LmOVA) and boosts inflammatory IFN-gamma, TNF alpha, and IL-2 cytokine recall responses. Adoptive transfer experiments using Nr2f6(-/-) OT-I T-cells showed that the augmented memory formation is CD8(+) T-cell intrinsic. Although the relative difference between the Nr2f6(+/+) and Nr2f6(-/-) OT-I memory compartment declines over time, Nr2f6-deficient OT-I memory T cells mount significantly enhanced IFN-gamma responses upon reinfection with increased clonal expansion and improved host antigen-specific CD8(+) T-cell responses. Following a secondary adoptive transfer into naive congenic mice, Nr2f6-deficient OT-I memory T cells are superior in clearing LmOVA infection. Finally, we show that the commitment to enhanced memory within Nr2f6-deficient OT-I T cells is established in the early phases of the antibacterial immune response and is IFN-gamma mediated. IFN-gamma blocking normalized MPEC formation of Nr2f6-deficient OT-I T cells. Thus, deletion or pharmacological inhibition of NR2F6 in antigen-specific CD8(+) T cells may have therapeutic potential for enhancing early IFN-gamma production and consequently the functionality of memory CD8(+) T cells in vivo.

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  • 7.
    Li, Xinxiao
    et al.
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China; Zhengzhou Univ, Dept Neurosurg, Affiliated Hosp 5, Zhengzhou, Henan, Peoples R China; Ningxia Med Univ, Gen Hosp, Dept Neurosurg, Yinchuan, Ningxia, Peoples R China.
    Guo, Shengnan
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China.
    Xu, Siying
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China; Ningxia Med Univ, Gen Hosp, Dept Neurosurg, Yinchuan, Ningxia, Peoples R China.
    Chen, Zhangping
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China.
    Wang, Lei
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China; Ningxia Med Univ, Gen Hosp, Dept Neurosurg, Yinchuan, Ningxia, Peoples R China.
    Ding, Jiangwei
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China; Ningxia Med Univ, Gen Hosp, Dept Neurosurg, Yinchuan, Ningxia, Peoples R China.
    Huo, Junming
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China.
    Xiao, Lifei
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China; Ningxia Med Univ, Gen Hosp, Dept Neurosurg, Yinchuan, Ningxia, Peoples R China.
    He, Zhenquan
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China.
    Wang, Feng
    Zhejiang Univ, Affiliated Hosp 1, Dept Neurosurg, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Sun, Tao
    Ningxia Med Univ, Ningxia Key Lab Cerebrocranial Dis, Incubat Base Natl Key Lab, Yinchuan, Ningxia, Peoples R China; Ningxia Med Univ, Gen Hosp, Dept Neurosurg, Yinchuan, Ningxia, Peoples R China.
    Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice2021In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 12, no 6, article id 553Article in journal (Refereed)
    Abstract [en]

    Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V–VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.

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  • 8.
    Lu, Xi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Zhong, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, Sichuan, China.
    Lindell, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Veanes, Margus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Guo, Jing
    Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore.
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Salehi, Maede
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Chen, Xingqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Zhang, Xiaonan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Identification of ATF3 as a novel protective signature of quiescent colorectal tumor cells2023In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 14, no 10, article id 676Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.

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  • 9.
    Ma, Jing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Quijano-Rubio, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Hosp, Mol Neurooncol Lab, Dept Neurol, CH-8091 Zurich, Switzerland;Univ Zurich, CH-8091 Zurich, Switzerland.
    Martikainen, Miika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer2020In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 11, no 1, article id 48Article in journal (Refereed)
    Abstract [en]

    Oncolytic viruses have the potential to induce immunogenic cell death (ICD) that may provoke potent and long-lasting anti-cancer immunity. Here we aimed to characterize the ICD-inducing ability of wild-type Adenovirus (Ad), Semliki Forest virus (SFV) and Vaccinia virus (VV). We did so by investigating the cell death and immune-activating properties of virus-killed tumor cells. Ad-infection of tumor cells primarily activates autophagy, but also activate events of necroptotic and pyroptotic cell death. SFV infection on the other hand primarily activates immunogenic apoptosis while VV activates necroptosis. All viruses mediated lysis of tumor cells leading to the release of danger-associated molecular patterns, triggering of phagocytosis and maturation of dendritic cells (DCs). However, only SFV-infected tumor cells triggered significant T helper type 1 (Th1)-cytokine release by DCs and induced antigen-specific T-cell activation. Our results elucidate cell death processes activated upon Ad, SFV, and VV infection and their potential to induce T cell-mediated anti-tumor immune responses. This knowledge provides important insight for the choice and design of therapeutically successful virus-based immunotherapies.

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  • 10. Maximyuk, O.
    et al.
    Khmyz, V.
    Lindskog, C-J
    Vukojevic, V.
    Ivanova, T.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hauser, K. F.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Krishtal, O.
    Plasma membrane poration by opioid neuropeptides: a possible mechanism of pathological signal transduction2015In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 6, article id e1683Article in journal (Refereed)
    Abstract [en]

    Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (similar to 2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.

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  • 11.
    Melo, Fabio R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Martin, Sebastin Santosh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sommerhoff, Christian P.
    Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Lab Med, Munich, Germany.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Exosome-mediated uptake of mast cell tryptase into the nucleus of melanoma cells: a novel axis for regulating tumor cell proliferation and gene expression2019In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 10, article id 659Article in journal (Refereed)
    Abstract [en]

    It is well established that mast cell accumulation accompanies most malignancies. However, the knowledge of how mast cells functionally impact on tumors is still rudimentary. Here we addressed this issue and show that mast cells have anti-proliferative activity on melanoma cells and that this effect is dependent on tryptase, a tetrameric protease stored in mast cell granules. Mechanistically, tryptase was found to be endocytosed by melanoma cells as cargo of DNA-coated exosomes released from melanoma cells, followed by transport to the nucleus. In the nucleus, tryptase executed clipping of histone 3 and degradation of Lamin B1, accompanied by extensive nuclear remodeling. Moreover, tryptase degraded hnRNP A2/B1, a protein involved in mRNA stabilization and interaction with non-coding RNAs. This was followed by downregulated expression of the oncogene EGR1 and of multiple non-coding RNAs, including oncogenic species. Altogether, these findings establish a new principle for regulation of tumor cell proliferation.

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  • 12.
    Milosch, N
    et al.
    Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
    Tanriöver, G
    Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
    Kundu, A
    Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
    Rami, A
    Institute of Cellular and Molecular Anatomy (Anatomie III), Frankfurt University Hospital, Frankfurt am Main, Germany.
    Francois, J-C
    Inserm and Sorbonne Universities, UPMC, Research Center Saint-Antoine, Paris, France.
    Baumkötter, F
    Division of Human Biology and Human Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany.
    Weyer, SW
    Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
    Samanta, Ayan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Department of Pharmaceutical Chemistry, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
    Jäschke, A
    Department of Pharmaceutical Chemistry, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
    Brod, F
    Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany.
    Buchholz, CJ
    Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany.
    Kins, S
    Division of Human Biology and Human Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany.
    Behl, C
    Institute for Pathobiochemistry, University Medical Center, Mainz University, Mainz, Germany.
    Müller, UC
    Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
    Kögel, D
    Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
    Holo-APP and G-protein-mediated signaling are required for sAPPa-induced activation of the Akt survival pathway2014In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 5, article id e1391Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence indicates that loss of physiologic amyloid precursor protein (APP) function leads to reduced neuronal plasticity, diminished synaptic signaling and enhanced susceptibility of neurons to cellular stress during brain aging. Here we investigated the neuroprotective function of the soluble APP ectodomain sAPPα (soluble APPα), which is generated by cleavage of APP by α-secretase along the non-amyloidogenic pathway. Recombinant sAPPα protected primary hippocampal neurons and SH-SY5Y neuroblastoma cells from cell death induced by trophic factor deprivation. We show that this protective effect is abrogated in neurons from APP-knockout animals and APP-depleted SH-SY5Y cells, but not in APP-like protein 1- and 2- (APLP1 and APLP2) depleted cells, indicating that expression of membrane-bound holo-APP is required for sAPPα-dependent neuroprotection. Trophic factor deprivation diminished the activity of the Akt survival pathway. Strikingly, both recombinant sAPPα and the APP-E1 domain were able to stimulate Akt activity in wild-type (wt) fibroblasts, SH-SY5Y cells and neurons, but failed to rescue in APP-deficient neurons or fibroblasts. The ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) inhibitor GI254023X exacerbated neuron death in organotypic (hippocampal) slice cultures of wt mice subjected to trophic factor and glucose deprivation. This cell death-enhancing effect of GI254023X could be completely rescued by applying exogenous sAPPα. Interestingly, sAPPα-dependent Akt induction was unaffected in neurons of APP-ΔCT15 mice that lack the C-terminal YENPTY motif of the APP intracellular region. In contrast, sAPPα-dependent rescue of Akt activation was completely abolished in APP mutant cells lacking the G-protein interaction motif located in the APP C-terminus and by blocking G-protein-dependent signaling with pertussis toxin. Collectively, our data provide new mechanistic insights into the physiologic role of APP in antagonizing neurotoxic stress: they suggest that cell surface APP mediates sAPPα-induced neuroprotection via G-protein-coupled activation of the Akt pathway.

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  • 13. Mohell, N.
    et al.
    Alfredsson, J.
    Fransson, A.
    Uustalu, M.
    Bystrom, S.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bykov, V. J. N.
    Bjorklund, U.
    Wiman, K. G.
    APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells2015In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 6, article id e1794Article in journal (Refereed)
    Abstract [en]

    Two main causes of platinum resistance are mutation in the tumor suppressor gene TP53 and drug-induced increase in intracellular glutathione concentration. Mutations in TP53 occur in about 50% of human tumors. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and restores its wildtype conformation. Here, we show that MQ also binds to cysteine in glutathione, thus decreasing intracellular free glutathione concentration. We also show that treatment with APR-246 completely restores the cisplatin and doxorubicin sensitivity to p53-mutant drug-resistant ovarian cancer cells. We propose that this unique ability of APR-246/MQ to bind to cysteines in both mutant p53 and glutathione has a key role in the resensitization as well as in the outstanding synergistic effects observed with APR-246 in combination with platinum compounds in ovarian cancer cell lines and primary cancer cells. However, MQ binding to cysteines in other targets, for example, thioredoxin reductase, may contribute as well. Strong synergy was also observed with the DNA-damaging drugs doxorubicin and gemcitabine, while additive effects were found with the taxane docetaxel. Our results provide a strong rationale for the ongoing clinical study with APR-246 in combination with platinum-based therapy in patients with p53-mutant recurrent high-grade serous (HGS) ovarian cancer. More than 96% of these patients carry TP53 mutations. Combined treatment with APR-246 and platinum or other DNA-damaging drugs could allow dramatically improved therapy of a wide range of therapy refractory p53 mutant tumors.

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  • 14. Moreno-Càceres, J
    et al.
    Caja, Laia
    Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Mainez, J
    Mayoral, R
    Martín-Sanz, P
    Moreno-Vicente, R
    Del Pozo, M Á
    Dooley, S
    Egea, G
    Fabregat, I
    Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM172014In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 5, article id e1326Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF-β) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1(-/-) hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-β, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-β-induced survival signals in Cav1(-/-) hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β was impaired in Cav1(-/-) hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1(-/-) hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1(+/+) cells, which was not the case in Cav1(-/-) cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells.

  • 15.
    Nylund, Patrick
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Atienza Párraga, Alba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    De Bruyne, Elke
    Menu, Eline
    Garrido-Zabala, Berta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ma, Anqi
    Jin, Jian
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vanderkerken, Karin
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma2021In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 12, no 2, article id 167Article in journal (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.

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  • 16.
    Pejler, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Frisk, Jun Mei Hu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjöström, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Paivandy, Aida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öhrvik, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Acidic pH is essential for maintaining mast cell secretory granule homeostasis2017In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 8, article id e2785Article in journal (Refereed)
    Abstract [en]

    It has been recognized for a long time that the secretory granules of mast cells are acidic, but the functional importance of maintaining an acidic pH in the mast cell granules is not fully understood. Here we addressed this issue by examining the effects of raising the pH of the mast cell secretory granules. Mast cells were incubated with bafilomycin A1, an inhibitor of the vacuolar-type ATPase proton pump. Supporting a role of vacuolar-type ATPase in mast cell granule acidification, bafilomycin A1 treatment caused a robust increase in granule pH. This was accompanied by marked effects on mast cell granules, including swelling and acquisition of vacuole-like morphology. Moreover, bafilomycin A1 caused extensive, yet selective effects on the granule content. These included aberrant processing of pro-carboxypeptidase A3 and a reduction in the level of intracellular histamine, the latter being accompanied by an increase in extracellular histamine. In contrast, the storage of beta-hexosaminidase, a prototype lysosomal hydrolase known to be stored in mast cell granules, was not affected by abrogation of granule acidification. Moreover, bafilomycin A1 caused a reduction of tryptase enzymatic activity and appearance of tryptase degradation products. Tryptase inhibition prevented the formation of such degradation products, suggesting that the pH elevation causes tryptase to undergo autoproteolysis. Taken together, our findings reveal that mast cell secretory granule homeostasis is critically dependent on an acidic milieu.

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  • 17.
    Pierozan, Paula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Stockholm Univ, Dept Environm Sci & Analyt Chem, Sci Life Lab, S-11418 Stockholm, Sweden.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Stockholm Univ, Dept Environm Sci & Analyt Chem, Sci Life Lab, S-11418 Stockholm, Sweden.
    Mitotically heritable effects of BMAA on striatal neural stem cell proliferation and differentiation2019In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 10, article id 478Article in journal (Refereed)
    Abstract [en]

    The widespread environmental contaminant beta-methylamino-L-alanine (BMAA) is a developmental neurotoxicant that can induce long-term learning and memory deficits. Studies have shown high transplacental transfer of 3H-BMAA and a significant uptake in fetal brain. Therefore, more information on how BMAA may influence growth and differentiation of neural stem cells is required for assessment of the risk to the developing brain. The aim of this study was to investigate direct and mitotically inherited effects of BMAA exposure using primary striatal neurons and embryonic neural stem cells. The neural stem cells were shown to be clearly more susceptible to BMAA exposure than primary neurons. Exposure to 250 mu M BMAA reduced neural stem cell proliferation through apoptosis and G2/M arrest. At lower concentrations (50-100 mu M), not affecting cell proliferation, BMAA reduced the differentiation of neural stem cells into astrocytes, oligodendrocytes, and neurons through glutamatergic mechanisms. Neurons that were derived from the BMAA-treated neuronal stem cells demonstrated morphological alterations including reduced neurite length, and decreased number of processes and branches per cell. Interestingly, the BMAA-induced changes were mitotically heritable to daughter cells. The results suggest that early-life exposure to BMAA impairs neuronal stem cell programming, which is vital for development of the nervous system and may result in long-term consequences predisposing for both neurodevelopmental disorders and neurodegenerative disease later in life. More attention should be given to the potential adverse effects of BMAA exposure on brain development.

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  • 18.
    Tsirigoti, Chrysoula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ali, Mohamad Moustafa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maturi, Varun
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Loss of SNAI1 induces cellular plasticity in invasive triple-negative breast cancer cells2022In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 13, no 9, article id 832Article in journal (Refereed)
    Abstract [en]

    The transcription factor SNAI1 mediates epithelial-mesenchymal transition, fibroblast activation and controls inter-tissue migration. High SNAI1 expression characterizes metastatic triple-negative breast carcinomas, and its knockout by CRISPR/Cas9 uncovered an epithelio-mesenchymal phenotype accompanied by reduced signaling by the cytokine TGFβ. The SNAI1 knockout cells exhibited plasticity in differentiation, drifting towards the luminal phenotype, gained stemness potential and could differentiate into acinar mammospheres in 3D culture. Loss of SNAI1 de-repressed the transcription factor FOXA1, a pioneering factor of mammary luminal progenitors. FOXA1 induced a specific gene program, including the androgen receptor (AR). Inhibiting AR via a specific antagonist regenerated the basal phenotype and blocked acinar differentiation. Thus, loss of SNAI1 in the context of triple-negative breast carcinoma cells promotes an intermediary luminal progenitor phenotype that gains differentiation plasticity based on the dual transcriptional action of FOXA1 and AR. This function of SNAI1 provides means to separate cell invasiveness from progenitor cell de-differentiation as independent cellular programs.

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  • 19. Westerberg, C Möller
    et al.
    Hägglund, Hans
    Department of Hematology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, G
    Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation2012In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 3, p. e417-Article in journal (Refereed)
    Abstract [en]

    The majority of patients with systemic mastocytosis exhibit a D816V mutation in the activating loop of the Kit receptor expressed on mast cells. The Kit ligand regulates mast cell survival by transcriptional repression of the proapoptotic BH3-only protein Bim and by promoting Bim phosphorylation that makes it vulnerable for proteasomal-dependent degradation. We investigated here whether prevention of Bim degradation by a proteasomal inhibitor, MG132, would induce apoptosis in mast cells with the D816V mutation. Human umbilical cord blood-derived mast cells (CBMCs) with wild-type (wt) Kit and two different subclones of the human mast cell line-1 (HMC-1) were used for the study: HMC-1.1 with the V560G mutation in the juxtamembrane domain and HMC-1.2 carrying the V560G mutation together with the D816V mutation. MG132 at 1 μM induced apoptosis in all cell types, an effect accompanied by increased BH3-only proapoptotic protein Bim. The raise of Bim was accompanied by caspase-3 activation, and a caspase-3 inhibitor reduced MG132-induced apoptosis. Further, MG132 caused a reduction of activated Erk, a negative regulator of Bim expression, and thus Bim upregulation. We conclude that decreased phosphorylation and increased levels of Bim overcome the prosurvival effect of the D816V mutation and that the results warrant further investigations of the clinical effects of proteasomal inhibition in systemic mastocytosis.

  • 20. Xu, J.
    et al.
    Eriksson, S. E.
    Cebula, M.
    Sandalova, T.
    Hedstrom, E.
    Pader, I.
    Cheng, Q.
    Myers, C. R.
    Antholine, W. E.
    Nagy, P.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Selivanova, G.
    Lindqvist, Y.
    Arner, E. S. J.
    The conserved Trp114 residue of thioredoxin reductase 1 has a redox sensor-like function triggering oligomerization and crosslinking upon oxidative stress related to cell death2015In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 6, article id e1616Article in journal (Refereed)
    Abstract [en]

    The selenoprotein thioredoxin reductase 1 (TrxR1) has several key roles in cellular redox systems and reductive pathways. Here we discovered that an evolutionarily conserved and surface-exposed tryptophan residue of the enzyme (Trp114) is excessively reactive to oxidation and exerts regulatory functions. The results indicate that it serves as an electron relay communicating with the FAD moiety of the enzyme, and, when oxidized, it facilitates oligomerization of TrxR1 into tetramers and higher multimers of dimers. A covalent link can also be formed between two oxidized Trp114 residues of two subunits from two separate TrxR1 dimers, as found both in cell extracts and in a crystal structure of tetrameric TrxR1. Formation of covalently linked TrxR1 subunits became exaggerated in cells on treatment with the pro-oxidant p53-reactivating anticancer compound RITA, in direct correlation with triggering of a cell death that could be prevented by antioxidant treatment. These results collectively suggest that Trp114 of TrxR1 serves a function reminiscent of an irreversible sensor for excessive oxidation, thereby presenting a previously unrecognized level of regulation of TrxR1 function in relation to cellular redox state and cell death induction.

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  • 21.
    Zhang, Qiang
    et al.
    Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden..
    Balourdas, Dimitrios-Ilias
    Goethe Univ, Inst Pharmaceut Chem, Max Laue Str 9, D-60438 Frankfurt, Germany.;Buchmann Inst Mol Life Sci, Max Laue Str 15, D-60438 Frankfurt, Germany..
    Baron, Bruno
    Inst Pasteur, Ctr Ressources & Rech Technol C2RT, Plateforme Biophys Mol, F-75015 Paris, France..
    Senitzki, Alon
    Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel..
    Haran, Tali E.
    Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel..
    Wiman, Klas G.
    Karolinska Inst, Bioclinicum, Dept Oncol Pathol, Stockholm, Sweden..
    Soussi, Thierry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. UPMC Univ Paris 06, Sorbonne Univ, F-75005 Paris, France..
    Joerger, Andreas C.
    Goethe Univ, Inst Pharmaceut Chem, Max Laue Str 9, D-60438 Frankfurt, Germany.;Buchmann Inst Mol Life Sci, Max Laue Str 15, D-60438 Frankfurt, Germany..
    Evolutionary history of the p53 family DNA-binding domain: insights from an Alvinella pompejana homolog2022In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 13, no 3, article id 214Article in journal (Refereed)
    Abstract [en]

    The extremophile Alvinella pompejana, an annelid worm living on the edge of hydrothermal vents in the Pacific Ocean, is an excellent model system for studying factors that govern protein stability. Low intrinsic stability is a crucial factor for the susceptibility of the transcription factor p53 to inactivating mutations in human cancer. Understanding its molecular basis may facilitate the design of novel therapeutic strategies targeting mutant p53. By analyzing expressed sequence tag (EST) data, we discovered a p53 family gene in A. pompejana. Protein crystallography and biophysical studies showed that it has a p53/p63-like DNA-binding domain (DBD) that is more thermostable than all vertebrate p53 DBDs tested so far, but not as stable as that of human p63. We also identified features associated with its increased thermostability. In addition, the A. pompejana homolog shares DNA-binding properties with human p53 family DBDs, despite its evolutionary distance, consistent with a potential role in maintaining genome integrity. Through extensive structural and phylogenetic analyses, we could further trace key evolutionary events that shaped the structure, stability, and function of the p53 family DBD over time, leading to a potent but vulnerable tumor suppressor in humans.

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