Pidder Jansen-Dürr

University of Innsbruck, Innsbruck, Tyrol, Austria

Are you Pidder Jansen-Dürr?

Claim your profile

Publications (117)550.61 Total impact

  • Huaije Bu · Giorgia Baraldo · Günter Lepperdinger · Pidder Jansen-Dürr
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are a group of small non-coding executor RNAs. Their function as key modulators of cellular senescence has been widely recognized recently. By cross-comparing several human aging models we previously identified dozens of miRNAs being differentially regulated during aging. Here the functions of two miRNAs, mir-24 and mir-424, were investigated in an oxidative stress-induced fibroblast premature senescence model. Using pre-miRNA precursors, miRNAs were overexpressed in cells undergoing premature senescence induced by oxidative stress. More senescent cells were observed in mir-24 transfected cells. p53 was upregulated in mir-24 overexpressing cells, but downregulated in mir-424 overexpressing cells. DNA topoisomerase I (TOP1), an enzyme controlling DNA topology, was identified as a target of mir-24, whose expression was induced by oxidative stress. Knocking down TOP1 induced cellular senescence. These results suggest that mir-24 activity propagates stress-induced senescence by down regulating TOP1.
    No preview · Article · Dec 2015 · Experimental gerontology

  • No preview · Conference Paper · Aug 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The fumarylacetoacetate hydrolase (FAH) protein superfamily of metabolic enzymes comprises a diverse set of enzymatic functions, including ß-diketone hydrolases, decarboxylases, and isomerases. Of note, the FAH superfamily includes many prokaryotic members with very distinct functions that lack homologs in eukaryotes. A prokaryotic member of the FAH superfamily, referred to as Cg1458, was shown to encode a soluble oxaloacetate decarboxylase (ODx). Based on sequence homologies to Cg1458, we recently identified human FAH domain containing protein-1 (FAHD1) as the first eukaryotic oxaloacetate decarboxylase. The physiological functions of ODx in eukaryotes remain unclear. Here we have probed the function of fahd-1, the nematode homolog of FAHD1, in the context of an intact organism. We found that mutation of fahd-1 resulted in reduced brood size, a deregulation of the egg laying process and a severe locomotion deficit, characterized by a reduced frequency of body bends, reduced exploratory movements and reduced performance in an endurance exercise test. Notably, mitochondrial function was altered in the fahd-1(tm5005) mutant strain, as shown by a reduction of mitochondrial membrane potential and a reduced oxygen consumption of fahd-1(tm5005) animals. Mitochondrial dysfunction was accompanied by lifespan extension in worms grown at elevated temperature; however, unlike in mutant worms with a defect in the electron transport chain, the mitochondrial unfolded protein response was not upregulated in worms upon inactivation of fahd-1. Together these data establish a role of fahd-1 to maintain mitochondrial function and consequently physical activity in nematodes.
    Full-text · Article · Aug 2015 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: An increase in the number of older people experiencing disability and dependence is a critical aspect of the demographic change that will emerge within Europe due to the rise in life expectancy. In this scenario, prevention of these conditions is crucial for the well-being of older citizens and for the sustainability of our healthcare systems. Thus, the diagnosis and management of conditions like frailty, which identifies the people at the highest risk for developing those adverse outcomes, is of critical relevance. Currently, assessment of frailty relies primarily on measuring functional parameters, which have limited clinical utility. In this viewpoint article, we describe the FRAILOMIC Initiative, an international, large-scale, multi-endpoint, community- and clinic-based research study funded by the European Commission. The aim of the study is to develop validated measures, comprising both classic and ‘omics-based' laboratory biomarkers, which can predict the risk of frailty, improve the accuracy of its diagnosis in clinical practice and provide a prognostic forecast on the evolution from frailty to disability. The initiative includes eight established cohorts of older adults, encompassing >75,000 subjects, most of whom (∼70%) are aged >65 years. Data on function, nutritional status and exercise habits have been collected, and cardiovascular health has been evaluated at baseline. Subjects will be stratified as ‘non-frail' or ‘frail' using Fried's definition, all adverse outcomes of interest will be recorded and differentially expressed biomarkers associated with the risk of frailty will be identified. Genomic, proteomic and transcriptomic investigations will be carried out using array-based systems. As circulating microRNAs in plasma have been identified in the context of senescence, ageing and age-associated diseases, a miRNome-wide analysis will also be undertaken to identify a miRNA-based signature of frailty. Blood concentrations of secreted proteins known to be upregulated significantly in senescent endothelial cells and other hypothesis-driven biomarkers will be measured using ELISAs. The FRAILOMIC Initiative aims to issue a series of interim scientific reports as key results emerge. Ultimately, it is hoped that this study will contribute to the development of new clinical tools, which may help individuals to enjoy an old age that is healthier and free from disability.
    No preview · Article · Jul 2015 · Gerontology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Subchronic oxidative stress and inflammation are being increasingly implicated in the pathogenesis of numerous diseases, such as Alzheimeŕs or Parkinsońs disease. This study was designed to evaluate the potential protective role of α7 nicotinic receptor activation in an in vitro model of neurodegeneration based on subchronic oxidative stress. Rat organotypic hippocampal cultures (OHCs) were exposed for 4 days to low concentration of lipopolysaccharide (LPS) and the complex III mitochondrial blocker, antimycin-A. Antimycin-A (0.1μM) and lipopolysaccharide (1 ng/ml) caused low neurotoxicity on their own, measured as propidium iodide fluorescence in CA1 and CA3 regions. However, their combination (LPS/AA) caused a greater detrimental effect, in addition to mitochondrial depolarization, overproduction of reactive oxygen species (ROS) and Nox4 overexpression. Antimycin-A per se increased ROS and mitochondrial depolarization, although these effects were significantly higher when combined with LPS. More interesting was the finding that exposure of OHCs to the combination of LPS/AA triggered aberrant protein aggregation, measured as thioflavin S immunofluorescence. The α7 nicotinic receptor agonist, PNU282987, prevented the neurotoxicity and the pathological hallmarks observed in the LPS/AA subchronic toxicity model (oxidative stress and protein aggregates); these effects were blocked by α-bungarotoxin and tin protoporphyrin, indicating the participation of α7 nAChRs and heme-oxygenase I induction. In conclusion, subchronic exposure of OHCs to low concentration of antimycin-A plus LPS reproduced pathological features of neurodegenerative disorders. α7 nAChR activation ameliorated these alterations by a mechanism involving heme-oxygenase I induction. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Biochemical pharmacology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The FRAILOMIC consortium (available at: was created and funded under the European FP7 framework in order to overcome these limitations. The consortium comprises seven small and medium-sized companies, six universities, two leading research centres, two hospital-based research groups and researches affiliated with the World Health Organization (WHO). The primary aim is to create a European network for developing clinical tools and validating biomarkers that can assist in the managed care of frailty. More specifically, a large number of molecular and biochemical biomarkers will be measured in as many as 75,000 participants, in order to develop predictive, diagnostic and prognostic models in the older general population and people at a higher risk of frailty. The analytical and diagnostic performance of these biomarkers will be compared against the current quality specifications to define whether the current techniques are suitable for use in this specific population. A selected set of biomarkers will then be validated prospectively and assessed to identify the best fit models, which will guide the development of panels of tests or risk estimation models to be used in the clinical setting. The homeostatic impairments of frailty will hence be assessed using a multidisciplinary approach within this network. Hopefully, the outcomes of this initiative will underline the important contribution of laboratory diagnostics for reducing the prevalence or severity of this increasingly frequent condition, thus resulting in large benefits for individuals, society and healthcare systems.
    Full-text · Article · Mar 2015 · Clinical Chemistry and Laboratory Medicine
  • [Show abstract] [Hide abstract]
    ABSTRACT: High-risk human papillomaviruses (HPV) are the main etiologic factor for the development of cervical cancer. Infections by these viruses have been detected in virtually all cervical cancers. C-33A is one of the rare cervical cancer derived cell lines considered as HPV-negative. Employing monoclonal antibodies raised against a conformational epitope of the HPV-16 E7 oncoprotein, we present evidence suggesting that E7-positive cells can be sporadically and transiently detected in C-33A cell cultures. Immunoblotting with affinity-purified rabbit polyclonal anti-HPV 16 E7 antisera and q-RT-PCR analysis suggest that these cells do probably not express HPV-16 E7. Moreover, we show that the HPV E7 protein level differs considerably between individual cells in cultures of several established cervical cancer cell lines. Our data suggest that expression of the E7 protein is variable in established cervical cancer cell lines including C-33A cells.
    No preview · Article · Oct 2014 · Virus Genes
  • Source

    Full-text · Article · May 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Author Summary Health- or lifespan-prolonging regimes would be beneficial at both the individual and the social level. Nevertheless, up to date only very few experimental settings have been proven to promote longevity in mammals. Among them is the reduction of food intake (caloric restriction) or the pharmacological administration of caloric restriction mimetics like rapamycin. The latter one, however, is accompanied by not yet fully estimated and undesirable side effects. In contrast, the limitation of one specific amino acid, namely methionine, which has also been demonstrated to elongate the lifespan of mammals, has the advantage of being a well applicable regime. Therefore, understanding the underlying mechanism of the anti-aging effects of methionine restriction is of crucial importance. With the help of the model organism yeast, we show that limitation in methionine drastically enhances autophagy, a cellular process of self-digestion that is also switched on during caloric restriction. Moreover, we demonstrate that this occurs in causal conjunction with an efficient pH decrease in the organelle responsible for the digestive capacity of the cell (the vacuole). Finally, we prove that autophagy-dependent vacuolar acidification is necessary for methionine restriction-mediated lifespan extension.
    Full-text · Article · May 2014 · PLoS Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Infections with high-risk human papillomaviruses (hrHPV) contribute to cervical carcinoma. The cdk inhibitor and tumor suppressor p16(INK4A) is consistently upregulated in cervical carcinoma cells for reasons that are poorly understood. We report here that downregulation of p16(INK4A)gene expression in three different cervical carcinoma cell lines reduced expression of the E7 oncogene, suggesting a positive feedback loop involving E7 and p16(INK4A). p16(INK4A) depletion induced cellular senescence in HeLa but not CaSki and MS-751 cervical carcinoma cells. This study demonstrates that the cdk inhibitor p16(INK4A), frequently used as surrogate marker for transforming infections by human papillomaviruses of the high-risk group, is required for high level expression of the E7 oncoproteins of HPV-16, HPV-18 and HPV-45 in cervical carcinoma cells. It is also demonstrated that depletion of p16(INK4A) induces senescence in HeLa but not CaSki or MS-751 cervical carcinoma cells.
    Preview · Article · Mar 2014 · Journal of Virology
  • Source

    Full-text · Dataset · Jan 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Cellular senescence can be induced by a variety of extrinsic stimuli, and sustained exposure to sunlight is a key factor in photoaging of the skin. Accordingly, irradiation of skin fibroblasts by UVB light triggers cellular senescence, which is thought to contribute to extrinsic skin aging, although molecular mechanisms are incompletely understood. Here, we addressed molecular mechanisms underlying UVB induced senescence of human diploid fibroblasts. Results We observed a parallel activation of the p53/p21WAF1 and p16INK4a/pRb pathways. Using genome-wide transcriptome analysis, we identified a transcriptional signature of UVB-induced senescence that was conserved in three independent strains of human diploid fibroblasts (HDF) from skin. In parallel, a comprehensive screen for microRNAs regulated during UVB-induced senescence was performed which identified five microRNAs that are significantly regulated during the process. Bioinformatic analysis of miRNA-mRNA networks was performed to identify new functional mRNA targets with high confidence for miR-15a, miR-20a, miR-20b, miR-93, and miR-101. Already known targets of these miRNAs were identified in each case, validating the approach. Several new targets were identified for all of these miRNAs, with the potential to provide new insight in the process of UVB-induced senescence at a genome-wide level. Subsequent analysis was focused on miR-101 and its putative target gene Ezh2. We confirmed that Ezh2 is regulated by miR-101 in human fibroblasts, and found that both overexpression of miR-101 and downregulation of Ezh2 independently induce senescence in the absence of UVB irradiation. However, the downregulation of miR-101 was not sufficient to block the phenotype of UVB-induced senescence, suggesting that other UVB-induced processes induce the senescence response in a pathway redundant with upregulation of miR-101. Conclusion We performed a comprehensive screen for UVB-regulated microRNAs in human diploid fibroblasts, and identified a network of miRNA-mRNA interactions mediating UVB-induced senescence. In addition, miR-101 and Ezh2 were identified as key players in UVB-induced senescence of HDF.
    Full-text · Article · Apr 2013 · BMC Genomics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Reactive oxygen species (ROS) generated by NADPH oxidases play an important role in cellular signal transduction regulating cell proliferation, survival and differentiation. NADPH oxidase 4 (Nox4) induces cellular senescence in human endothelial cells; however, intracellular targets for Nox4 remained elusive. Here we show that Nox4 induces mitochondrial dysfunction in human endothelial cells. Nox4 depletion induced alterations in mitochondrial morphology, stabilized mitochondrial membrane potential, and decreased production of hydrogen peroxide in mitochondria. High-resolution respirometry in permeabilized cells combined with native polyacrylamide gel electrophoresis demonstrated that Nox4 specifically inhibits the activity of mitochondrial electron transport chain complex I, and this was associated with a decreased concentration of complex I subunits. These data suggest a new pathway by which sustained Nox4 activity decreases mitochondrial function.
    No preview · Article · Mar 2013 · Biochemical Journal
  • [Show abstract] [Hide abstract]
    ABSTRACT: NADPH oxidases transport electrons from cytosolic NADPH through biological membranes to generate reactive oxygen species. NADPH oxidase 4, broadly expressed in humans, is an interesting pharmacological target, since its activity is deregulated in several diseases, including pulmonary fibrosis, diabetic nephropathy, and cardiac hypertrophy. Whereas several candidate NADPH oxidase 4 inhibitors were recently described, most of these compounds are either unspecific or toxic. Here we set out to identify new NADPH oxidase 4 inhibitors from edible plants, in an attempt to decrease the number of hits with toxic side effects. We screened a compound library prepared from edible plants for new bioactives with the ability to inhibit the activity of NADPH oxidase 4. Using both cell-based and cell-free assays, we identified several compounds with significant inhibitory activity towards NADPH oxidase 4. For selected compounds, the activity profile towards NADPH oxidase 2 and NADPH oxidase 5 was established, and controls were carried out to exclude general reactive oxygen species scavengers. A number of promising NADPH oxidase 4 inhibitors from edible plants was identified and characterised. Several new chemical entities are disclosed which act as NADPH oxidase 4 inhibitors, and the efficacies of our best hits, in particular several diarylheptanoids and lignans, are comparable to the best available pharmacological NADPH oxidase 4 inhibitors. These findings will provide valuable tools to study mechanisms of NADPH oxidase inhibition.
    No preview · Article · Jan 2013 · Planta Medica
  • [Show abstract] [Hide abstract]
    ABSTRACT: Proteasome is the main intracellular organelle involved in the proteolytic degradation of abnormal, misfolded, damaged or oxidized proteins (1, 2). Maintenance of proteasome activity was implicated in many key cellular processes, like cell's stress response (3), cell cycle regulation and cellular differentiation (4) or in immune system response (5). The dysfunction of the ubiquitin-proteasome system has been related to the development of tumors and neurodegenerative diseases (4, 6). Additionally, a decrease in proteasome activity was found as a feature of cellular senescence and organismal aging (7, 8, 9, 10). Here, we present a method to measure ubiquitin-proteasome activity in living cells using a GFP-dgn fusion protein. To be able to monitor ubiquitin-proteasome activity in living primary cells, complementary DNA constructs coding for a green fluorescent protein (GFP)-dgn fusion protein (GFP-dgn, unstable) and a variant carrying a frameshift mutation (GFP-dgnFS, stable (11)) are inserted in lentiviral expression vectors. We prefer this technique over traditional transfection techniques because it guarantees a very high transfection efficiency independent of the cell type or the age of the donor. The difference between fluorescence displayed by the GFP-dgnFS (stable) protein and the destabilized protein (GFP-dgn) in the absence or presence of proteasome inhibitor can be used to estimate ubiquitin-proteasome activity in each particular cell strain. These differences can be monitored by epifluorescence microscopy or can be measured by flow cytometry.
    No preview · Article · Nov 2012 · Journal of Visualized Experiments
  • Source
    Eva Albertini · Rafal Kozieł · Angela Dürr · Michael Neuhaus · Pidder Jansen-Dürr
    [Show abstract] [Hide abstract]
    ABSTRACT: Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescencein vitro, involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease.
    Preview · Article · Oct 2012 · Aging
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Defective DNA repair is widely acknowledged to negatively impact on healthy aging, since mutations in DNA repair factors lead to accelerated and premature aging. However, the opposite, namely if improved DNA repair will also increase the life or health span is less clear, and only few studies have tested if overexpression of DNA repair factors modulates life and health span in cells or organisms. Recently, we identified and characterized SNEVhPrp19/hPso4, a protein that plays a role in DNA repair and pre-mRNA splicing, and observed a doubling of the replicative life span upon ectopic overexpression, accompanied by lower basal DNA damage and apoptosis levels as well as an increased resistance to oxidative stress. Here we find that SNEVhPrp19/hPso4 is phosphorylated at S149 in an ataxia telangiectasia mutated protein (ATM)-dependent manner in response to oxidative stress and DNA double strand break inducing agents. By overexpressing wild-type SNEVhPrp19/hPso4 and a phosphorylation-deficient point-mutant, we found that S149 phosphorylation is necessary for mediating the resistance to apoptosis upon oxidative stress and is partially necessary for elongating the cellular life span. Therefore, ATM dependent phosphorylation of SNEVhPrp19/hPso4 upon DNA damage or oxidative stress might represent a novel axis capable of modulating cellular life span.
    Full-text · Article · Apr 2012 · Aging
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) regulates cell proliferation and survival by extracellular interaction and inactivation of the growth factor IGF-I. Beyond that, IGF-independent actions mediated by intracellular IGFBP-3 including nuclear-IGFBP-3, have also been described. We here show, using both confocal and electron microscopy and cell fractionation, that the extracellular addition of IGFBP-3 to living cells results in rapid uptake and nuclear delivery of IGFBP-3, by yet partly unknown mechanisms. IGFBP-3 is internalized through a dynamin-dependent pathway, traffics through endocytic compartments and is finally delivered into the nucleus. We observed docking of IGFBP-3 containing structures to the nuclear envelope and found IGFBP-3 containing dot-like structures to permeate the nuclear envelope. In summary, our findings establish the pathway by which this tumor suppressor protein is delivered from extracellular space to the nucleus.
    Full-text · Article · Apr 2012 · International Journal of Cancer
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Persistent infections by high-risk human papillomaviruses (HPVs) are the main etiological factor for cervical cancer, and expression of HPV E7 oncoproteins was suggested to be a potential marker for tumor progression. The objective of this study was to generate new reagents for the detection of the HPV18 E7 oncoprotein in cervical smears. Rabbit monoclonal antibodies against recombinant E7 protein of HPV type 18 (HPV18) were generated and characterized using Western blotting, epitope mapping, indirect immunofluorescence, and immunohistochemistry. One clone specifically recognizing HPV18 E7 was used for the development of a sandwich enzyme-linked immunosorbent assay (ELISA). The assay was validated using recombinant E7 proteins of various HPV types and lysates from E7-positive cervical carcinoma cells. A total of 14 HPV18 DNA-positive cervical swab specimens and 24 HPV DNA-negative-control specimens were used for the determination of E7 protein levels by the newly established sandwich ELISA. On the basis of the average absorbance values obtained from all 24 negative controls, a cutoff above which a clinical sample can be judged E7 positive was established. Significant E7 signals 6- to 30-fold over background were found in 7 out of 14 abnormal HPV18 DNA-positive cervical smear specimens. This feasibility study demonstrates for the first time that HPV18 E7 oncoprotein can be detected in cervical smears.
    Full-text · Article · Nov 2011 · Journal of clinical microbiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We demonstrate that HPV-16 E7 forms a complex with Miz-1. UV-induced expression of the CDK-inhibitor p21(Cip1) and subsequent cell cycle arrest depends upon endogenous Miz-1 in HPV-negative C33A cervical cancer cells containing mutated p53. Transient expression of E7 in C33A inhibits UV-induced expression of p21(Cip1) and overcomes Miz-1-induced G1-phase arrest. The C-terminal E7Δ79LEDLL83-mutant with reduced Miz-1-binding capacity was impaired in its capability to repress p21(Cip1) expression; whereas the pRB-binding-deficient E7C24G-mutant inhibited p21(Cip1) expression similar to wild-type E7. Using ChIP, we demonstrate that endogenous E7 is bound to the endogenous p21(Cip1) core-promoter in CaSki cells and RNAi-mediated knock down of Miz-1 abrogates E7-binding to the p21(Cip1) promoter. Co-expression of E7 with Miz-1 inhibited Miz-1-induced p21(Cip1) expression from the minimal-promoter via Miz-1 DNA-binding sites. Co-expression of E7Δ79LEDLL83 did not inhibit Miz-1-induced p21(Cip1) expression. E7C24G retained E7-wild-type capability to inhibit Miz-1-dependent transactivation. These findings suggest that HPV-16 E7 can repress Miz-1-induced p21(Cip1) gene expression.
    Full-text · Article · Nov 2011 · Virology

Publication Stats

6k Citations
550.61 Total Impact Points


  • 2004-2015
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 1998-2015
    • Austrian Academy of Sciences
      • Institute for Biomedical Aging Research
      Wien, Vienna, Austria
  • 2012
    • Institute of Molecular Biology
      Mayence, Rheinland-Pfalz, Germany
  • 2008-2011
    • Tiroler Krebsforschungsinstitut TKFI
      Innsbruck, Tyrol, Austria
  • 2010
    • University of Natural Resources and Life Science Vienna
      • Department für Biotechnologie
      Vienna, Vienna, Austria
  • 2009
    • University of Salzburg
      • Division of Genetics
      Salzburg, Salzburg, Austria
  • 2001
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
  • 1995
    • University of Cambridge
      • Department of Pathology
      Cambridge, England, United Kingdom
  • 1994
    • Danish Cancer Society
      København, Capital Region, Denmark