Hilde Nilsen

• Schiavi, Alfonso; Salveridou, Eva; Brinkmann, Vanessa; Shaik, Anjumara; Menzel, Ralph & Kalyanasundaram, Sumana [Vis alle 9 forfattere av denne artikkelen] (2023). Mitochondria hormesis delays aging and associated diseases in Caenorhabditis elegans impacting on key ferroptosis players. iScience. 26:(4). doi: 10.1016/j.isci.2023.106448. Fulltekst i vitenarkiv Vis sammendrag

  Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode Caenorhabditis elegans. Instead, sub-lethal iron depletion extends C. elegans lifespan. Hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage across species but it has low feasible application. In this study, we assessed the potential beneficial effects of genetic and chemical interventions acting via mild iron instead of oxygen depletion. We show that limiting iron availability in C. elegans through frataxin silencing or the iron chelator bipyridine, similar to hypoxia preconditioning, protects against hypoxia-, age-, and proteotoxicity-induced neuromuscular deficits. Mechanistically, our data suggest that the beneficial effects elicited by frataxin silencing are in part mediated by counteracting ferroptosis, a form of non-apoptotic cell death mediated by iron-induced lipid peroxidation. This is achieved by impacting on different key ferroptosis players and likely via gpx-independent redox systems. We thus point to ferroptosis inhibition as a novel potential strategy to promote healthy aging.

• Gómez-Orte, Eva; Sáenz-Narciso, Beatriz; Zheleva, Angelina; Ezcurra, Begoña; Toro, Maria de & López, Rosario [Vis alle 11 forfattere av denne artikkelen] (2019). Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes. PLoS Genetics. ISSN 1553-7390. 15(2). doi: 10.1371/journal.pgen.1007981. Fulltekst i vitenarkiv Vis sammendrag

  Gene expression is generally regulated by recruitment of transcription factors and RNA polymerase II (RNAP II) to specific sequences in the gene promoter region. The Integrator complex mediates processing of small nuclear RNAs (snRNAs) as well as the initiation and release of paused RNAP II at specific genes in response to growth factors. Here we show that in C. elegans, disruption of the Integrator complex leads to transcription of genes located downstream of the snRNA loci via a non-conventional transcription mechanism based on the lack of processing of the snRNAs. RNAP II read-through generates long chimeric RNAs containing snRNA, the intergenic region and the mature mRNA of the downstream gene located in sense. These chimeric sn-mRNAs remain as untranslated long non-coding RNAs, in the case of U1- and U2-derived sn-mRNAs, but can be translated to proteins in the case of SL-derived sn-mRNAs. The transcriptional effect caused by disruption of the Integrator complex is not restricted to genes located downstream of the snRNA loci but also affects key regulators of signal transduction such as kinases and phosphatases. Our findings highlight that these transcriptional alterations may be behind the correlation between mutations in the Integrator complex and tumor transformation.

• Lirussi, Lisa; Antoniali, Giulia; D'Ambrosio, Chiara; Scaloni, Andrea; Nilsen, Hilde & Tell, Gianluca (2016). APE1 polymorphic variants cause persistent genomic stress and affect cancer cell proliferation. OncoTarget. 7(18), s. 26293–26306. doi: 10.18632/oncotarget.8477. Fulltekst i vitenarkiv Vis sammendrag

  Apurinic/apyrimidinic endonuclease 1 (APE1) is the main mammalian AP-endonuclease responsible for the repair of endogenous DNA damage through the base excision repair (BER) pathway. Molecular epidemiological studies have identified several genetic variants associated with human diseases, but a well-defined functional connection between mutations in APE1 and disease development is lacking. In order to understand the biological consequences of APE1 genetic mutations, we examined the molecular and cellular consequences of the selective expression of four non-synonymous APE1 variants (L104R, R237C, D148E and D283G) in human cells. We found that D283G, L104R and R237C variants have reduced endonuclease activity and impaired ability to associate with XRCC1 and DNA polymerase β, which are enzymes acting downstream of APE1 in the BER pathway. Complementation experiments performed in cells, where endogenous APE1 had been silenced by shRNA, showed that the expression of these variants resulted in increased phosphorylation of histone H2Ax and augmented levels of poly(ADP-ribosyl)ated (PAR) proteins. Persistent activation of DNA damage response markers was accompanied by growth defects likely due to combined apoptotic and autophagic processes. These phenotypes were observed in the absence of exogenous stressors, suggesting that chronic replication stress elicited by the BER defect may lead to a chronic activation of the DNA damage response. Hence, our data reinforce the concept that non-synonymous APE1 variants present in the human population may act as cancer susceptibility alleles.

• Meyer, Benedicte; Nguyen, Chinh Bkrong Thi Thuy; Moen, Aurora; Fagermoen, Frode Even; Sulheim, Dag & Nilsen, Hilde [Vis alle 8 forfattere av denne artikkelen] (2015). Maintenance of Chronic Fatigue Syndrome (CFS) in young CFS patients is associated with the 5-HTTLPR and SNP rs25531 A > G Genotype. PLOS ONE. 10(10). doi: 10.1371/journal.pone.0140883. Fulltekst i vitenarkiv Vis sammendrag

  Earlier studies have shown that genetic variability in the SLC6A4 gene encoding the serotonin transporter (5-HTT) may be important for the re-uptake of serotonin (5-HT) in the central nervous system. In the present study we investigated how the 5-HTT genotype i.e. the short (S) versus long (L) 5-HTTLPR allele and the SNP rs25531 A > G affect the physical and psychosocial functioning in patients with chronic fatigue syndrome (CFS). All 120 patients were recruited from The Department of Paediatrics at Oslo University Hospital, Norway, a national referral center for young CFS patients (12–18 years). Main outcomes were number of steps per day obtained by an accelerometer and disability scored by the Functional Disability Inventory (FDI). Patients with the 5-HTT SS or SLG genotype had a significantly lower number of steps per day than patients with the 5-HTT LALG, SLA or LALA genotype. Patients with the 5-HTT SS or SLG genotype also had a significantly higher FDI score than patients with the 5-HTT LALG, SLA or LALA genotype. Thus, CFS patients with the 5-HTT SS or SLG genotype had worse 30 weeks outcome than CFS patients with the 5-HTT LALG, SLA or LALA genotype. The present study suggests that the 5-HTT genotype may be a factor that contributes to maintenance of CFS.

• Solberg, Rigmor; Smith, Robert; Almlöf, Maria; Tewolde, Eyassu Araia; Nilsen, Hilde & Johansen, Harald Thidemann (2014). Legumain expression, activity and secretion are increased during monocyte-to-macrophage differentiation and inhibited by atorvastatin. Biological chemistry. ISSN 1431-6730. 396(1), s. 71–80. doi: 10.1515/hsz-2014-0172. Fulltekst i vitenarkiv
• Fang, Evandro Fei; Scheibye-Knudsen, Morten; Brace, Lear E; Kassahun, Henok; Sengupta, Tanima & Nilsen, Hilde [Vis alle 9 forfattere av denne artikkelen] (2014). Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell. ISSN 0092-8674. 157(4), s. 882–896. doi: 10.1016/j.cell.2014.03.026. Fulltekst i vitenarkiv
• Solberg, Rigmor; Smith, Robert; Almlöf, Maria; Tewolde, Eyassu Araia; Nilsen, Hilde & Johansen, Harald Thidemann (2014). Atorvastatin inhibits processing, activity and secretion of legumain in macrophages. Biological chemistry. ISSN 1431-6730. 396(1), s. 71–80. doi: 10.1515/hsz-2014-0172. Fulltekst i vitenarkiv
• Sengupta, Tanima; Torgersen, Maria Lyngaas; Kassahun, Henok; Vellai, Tibor; Simonsen, Anne & Nilsen, Hilde (2013). Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy. Nature Communications. 4. doi: 10.1038/ncomms3674. Fulltekst i vitenarkiv
• Lans, Hannes; Lindvall, Jessica Margareta; Thijssen, K.; Karambelas, AE; Cupac, D & Fensgård, Øyvind [Vis alle 10 forfattere av denne artikkelen] (2013). DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals. Cell Death and Differentiation. ISSN 1350-9047. 20(12), s. 1709–1718. doi: 10.1038/cdd.2013.126. Fulltekst i vitenarkiv
• Arczewska, Katarzyna; Tomazella, Gisele Guicardi; Lindvall, Jessica M.; Kassahun, Henok; Maglioni, Silvia & Torgovnick, Alessandro [Vis alle 17 forfattere av denne artikkelen] (2013). Active Transcriptomic and Proteomic Reprogramming in the C. elegans Nucleotide Excision Repair Mutant xpa-1. Nucleic Acids Research (NAR). ISSN 0305-1048. 41(10), s. 5368–5381. doi: 10.1093/nar/gkt225. Fulltekst i vitenarkiv
• Smith, Robert; Johansen, Harald Thidemann; Nilsen, Hilde; Haugen, Mads Haugland; Pettersen, Solveig & Mælandsmo, Gunhild [Vis alle 8 forfattere av denne artikkelen] (2012). Intra- and extracellular regulation of activity and processing of legumain by cystatin E/M. Biochimie. ISSN 0300-9084. 94(12), s. 2590–2599. doi: 10.1016/j.biochi.2012.07.026. Fulltekst i vitenarkiv

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• Alrawaf, Firas; Nilsen, Hilde; Lunde, Ngoc Nguyen; Morland, Cecilie & Solberg, Rigmor (2022). The cysteine protease legumain in Parkinson’s disease. Fulltekst i vitenarkiv
• Antobreh, Alfreda Serwah; Lunde, Ngoc Nguyen; Nilsen, Hilde & Solberg, Rigmor (2022). Effects of conditioned media from skeletal muscle cells on metabolism and regulation of the cysteine protease legumain in differentiating osteoblasts. Fulltekst i vitenarkiv
• Ciyow, Nasra; Bosnjak, Tatjana; Nilsen, Hilde; Lunde, Ngoc Nguyen; Johansen, Harald Thidemann & Solberg, Rigmor (2020). Effekt av teriparatid på differensiering og regulering av cysteinproteaser i osteoblaster. Fulltekst i vitenarkiv
• Olsen, Kristine Løkke; Johansen, Harald Thidemann; Nilsen, Hilde; Solberg, Rigmor & Berg, Kristian (2020). Effekt av cysteinproteasen legumain på celleviabilitet etter fotodynamisk terapi. Fulltekst i vitenarkiv
• Mohanachandran, Arthii; Bosnjak, Tatjana; Nilsen, Hilde; Lunde, Ngoc Nguyen; Solberg, Rigmor & Johansen, Harald Thidemann (2020). Differensiering av RAW264.7 til osteoklaster og karakterisering av cysteinproteaser i osteoklaster. Fulltekst i vitenarkiv
• Awale, Mustafa; Bosnjak, Tatjana; Nilsen, Hilde; Solberg, Rigmor & Johansen, Harald Thidemann (2019). Effekten av kjønnshormoner på differensiering av stamceller til osteoblaster og regulering av cysteinproteasene legumain og cathepsin B. Fulltekst i vitenarkiv
• Bosnjak, Tatjana; Solberg, Rigmor; Arnekleiv, Guro L.; Nilsen, Hilde; Jafari, Abbas & Bassatne, A. [Vis alle 9 forfattere av denne artikkelen] (2019). Vitamin D3 upregulates legumain in the early phase of osteoblast differentiation. Fulltekst i vitenarkiv
• Gjonbalaj, Nora; Nilsen, Hilde; Solberg, Rigmor & Johansen, Harald Thidemann (2018). Effekt av inflammasjon på regulering av cysteinproteasene legumain og cathepsin B under differensiering av humane mesenkymale stamceller til osteoblaster. Fulltekst i vitenarkiv
• Abbas, Iram; Nilsen, Hilde; Johansen, Harald Thidemann & Solberg, Rigmor (2018). Deksametason hemmer differensiering av humane mesenkymale stamceller til osteoblaster og regulerer cysteinproteasene legumain og cathepsin B. Fulltekst i vitenarkiv
• Alsøe, Lene; Wennerstrøm, Anna; Liu, Yan; Esbensen, Qin Ying; Bjørseth, Randi & Penz, Christine [Vis alle 10 forfattere av denne artikkelen] (2017). Do APOBEC proteins contribute to genomic instability in colitis-associated colorectal cancer? Fulltekst i vitenarkiv
• Bosnjak, Tatjana; Hemati, Paya Diana; Nilsen, Hilde; Solberg, Rigmor & Johansen, Harald Thidemann (2017). Legumain as a target for proton pump inhibitors (PPIs): Importance for off-target effects of PPIs? Fulltekst i vitenarkiv
• Solberg, Rigmor; Bosnjak, Tatjana; Nilsen, Hilde; Jafari, Abbas; Kassem, Moustapha & Johansen, Harald Thidemann (2017). Regulation of legumain and cysteine cathepsins during differentiation of human bone marrow stromal cells towards osteoblasts. Fulltekst i vitenarkiv
• Arnekleiv, Guro L.; Nilsen, Hilde; Lunde, Ngoc Nguyen Dieu; Solberg, Rigmor & Johansen, Harald Thidemann (2017). Effekt av vitamin D3 på uttrykk, aktivitet og sekresjon av cysteinproteasen legumain studert i ulike cellemodeller. Fulltekst i vitenarkiv
• Hemati, Paya Diana; Bosnjak, Tatjana; Nilsen, Hilde; Lunde, Ngoc Nguyen Dieu; Johansen, Harald Thidemann & Solberg, Rigmor (2017). The Proton Pump Inhibitor Lansoprazole Inhibits Protease Activity of Legumain. Fulltekst i vitenarkiv
• Abdukadir, Nuriddin; Lunde, Ngoc Nguyen Dieu; Nilsen, Hilde; Solberg, Rigmor & Johansen, Harald Thidemann (2016). Regulering av cysteinproteaser ved differensiering av monocytter til makrofager. Fulltekst i vitenarkiv
• Lunde, Ngoc Nguyen Dieu; Nilsen, Hilde; Damgaard, Ingrid; Kasem, Roya; Solberg, Rigmor & Haugen, Mads Haugland [Vis alle 7 forfattere av denne artikkelen] (2015). Importance of glycosylation for legumain and cystatin E/M functions. Fulltekst i vitenarkiv
• Johansen, Harald Thidemann; Elyouncha, Inass; Lunde, Ngoc Nguyen Dieu; Williams, Rich; Solberg, Rigmor & Nilsen, Hilde [Vis alle 7 forfattere av denne artikkelen] (2015). Opposing effects of glucose on legumain and cysteine cathepsins. Fulltekst i vitenarkiv
• Johansen, Harald Thidemann; Solberg, Rigmor; Nilsen, Hilde & Smith, Robert (2013). Effects and interplay of legumain and cystatin E/M om migration and invasion of macrophages. Fulltekst i vitenarkiv
• Smith, Robert; Johansen, Harald Thidemann; Nilsen, Hilde & Solberg, Rigmor (2013). Effects and interplay of legumain and cystatin E/M on migration and invasion of macrophages. Fulltekst i vitenarkiv
• Ånonsen, Kjersti Bergh; Nilsen, Hilde; Smith, Robert; Johansen, Harald Thidemann & Solberg, Rigmor (2013). Regulering av legumain i samspillet mellom makrofager og kreftceller. Fulltekst i vitenarkiv
• Tina, Elvestrand; Åstrand, Ove Alexander; Smith, Robert; Rongved, Pål; Nilsen, Hilde & Solberg, Rigmor [Vis alle 7 forfattere av denne artikkelen] (2013). Cellular effects of a colchicine-prodrug cleaved by legumain. Fulltekst i vitenarkiv
• Smith, Robert; Johansen, Harald Thidemann; Nilsen, Hilde; Yassen, Islam M.; Haugen, Mads Haugland & Pettersen, Solveig [Vis alle 9 forfattere av denne artikkelen] (2012). SECRETION, INTERNALIZATION AND INTERPLAY OF LEGUMAIN AND CYSTATIN E/M. Fulltekst i vitenarkiv
• Johansen, Harald Thidemann; Smith, Robert; Tewolde, Eyassu; Nilsen, Hilde & Solberg, Rigmor (2011). ATORVASTATIN INHIBITS LEGUMAIN ACTIVITY IN AND PROLEGUMAIN SECRETION FROM HUMAN ACTIVATED MACROPHAGES. Fulltekst i vitenarkiv
• Smith, Robert; Johansen, Harald Thidemann; Nilsen, Hilde; Yassen, Islam M.; Haugen, Mads Haugland & Pettersen, Solveig J. [Vis alle 7 forfattere av denne artikkelen] (2011). SUBCELLULAR LOCALIZATION, INTERPLAY AND SECRETION OF LEGUMAIN AND CYSTATIN E/M IN HEK 293 CELLS. Fulltekst i vitenarkiv
• Solberg, Rigmor; Almlöf, Maria; Nilsen, Hilde; Ali, Zana Abdullrahman; Abrahamson, Magnus & Johansen, Harald Thidemann (2009). Asparaginyl endopeptidase activity is upregulated during differentiation of monocytes to macrophages but only partly mediated by legumain. Fulltekst i vitenarkiv
• Solberg, Rigmor; Nilsen, Hilde; Johansen, Harald Thidemann; Mælandsmo, Gunhild M. & Briggs, Jon (2007). SCREENING OF THE EXPRESSIONS OF LEGUMAIN AND ITS SPECIFIC INHIBITOR CYSTATIN M IN VARIOUS MELANOMA CELLS. Fulltekst i vitenarkiv
• Almlöf, Maria; Solberg, Rigmor; Nilsen, Hilde & Johansen, Harald Thidemann (2006). Legumain expression and activity is highly increased as monocytes differentiate toward macrophages. Fulltekst i vitenarkiv
• Fensgård, Øyvind & Nilsen, Hilde (2010). Global Genome Responses to DNA-Repair Deficiency Modulate Aging and Stress Response Pathways. Universitetet i Oslo. Fulltekst i vitenarkiv Vis sammendrag

  The genomes of all animals are constantly challenged by exogenous and endogenous sources of DNA damaging agents. UV radiation, chemicals, pollutants, and by-products of the cells’ own metabolism may damage the genetic material. Such damages are harmful to the animal as they may cause mutations or generate cytotoxic lesions, which in turn may lead to disease, cancer and aging. Protection of the genome is therefore of the utmost importance. To counteract such potential detrimental effects, all organisms have developed protective mechanisms such as antioxidants and DNA repair mechanisms. DNA excision repair proteins detect lesions in DNA, excise the damaged base and re-insert a correct base, thus maintaining the correct coding properties of the genome. Defects in DNA repair mechanisms may lead to cancer, neurodegeneration, other age-related pathologies or senescence. The nematode Caenorhabditis elegans (C. elegans) contains very few DNA glycosylases, which are the lesion-detecting proteins in DNA excision repair, compared to other animals and organisms. Analysis of all transcribed genes in DNA repair-deficient mutants in C. elegans revealed a global transcriptional response aimed at minimizing further damage to the genome. This involved a down-regulation of insulin-like signaling and an upregulation of antioxidants and stress response genes, similar to the response seen in both long-lived and old animals. This response seems to be conserved across different species as analysis of comparable mutants in the yeast Saccharomyces cerevisiae and mouse showed a similar response. Pathway reconstruction and literature mining suggests that this response is not elicited only by lack of repair per se, but rather from aberrant or attempted processing of lesions by other repair pathways than those normally repairing such lesions. This result in lesions that block the transcription of active genes and signal the transcription of other genes aimed at reducing further damage to DNA. Analysis of C. elegans mutants deficient in two different repair pathways revealed a completely different response with downregulation of Aurora-B and Polo-like kinase 1 signaling networks as well as downregulation of other DNA repair pathways. The mechanism and signaling origin of this response is yet unknown. Gene expression profiling is emerging as a powerful complementary tool to classical genetics and molecular analysis. By taking a systems biology approach, which takes into account the interplay between many pathways, gene expression profiling may aid in the interpretation of observed phenotypes and assist in the generation of new testable hypotheses.

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