Elke Ueberham

University of Leipzig, Leipzig, Saxony, Germany

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Publications (35)138.11 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Reduction of beta-catenin (CTNNB1) destroying complex components, e.g. adenomatous polyposis coli (APC), induces beta-catenin signaling and subsequently triggers activation of genes involved in proliferation and tumorigenesis. Though diminished expression of APC has organ specific and threshold dependent influence on the development of liver tumors in mice, the molecular basis is poorly understood. Therefore, a detailed investigation was conducted to determine the underlying mechanism in the development of liver tumors under reduced APC levels. Mouse liver at different developmental stages was analyzed in terms of beta-catenin target genes including Cyp2e1, Glul and Ihh using real-time RT-PCR, reporter gene assays and immunohistological methods with consideration of liver zonation. Data from human livers with mutations in APC derived from FAP patients were also included. Hepatocyte senescence was investigated by determining p16(INK4a) expression level, presence of senescence-associated beta-galactosidase (SA-beta-Gal) activity and assessing ploidy. A beta-catenin activation of hepatocytes does not always result in beta-catenin positivity but unexpectedly also in mixed and beta-catenin negative tumors. In summary, a senescence inducing program was found in hepatocytes with increased beta-catenin levels and a positive selection of hepatocytes lacking p16(INK4a), by epigenetic silencing, drives the development of liver tumors in mice with reduced APC expression (Apc(580S) mice). The lack of p16(INK4a) was also detected in liver tumors of mice with triggers other than APC reduction. Implications: Epigenetic silencing of p16(Ink4a) in selected liver cells bypassing senescence is a general principle for development of liver tumors with beta-catenin involvement in mice independent of the initial stimulus.
    Molecular Cancer Research 09/2014; 13(2). DOI:10.1158/1541-7786.MCR-14-0278-T · 4.50 Impact Factor
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    ABSTRACT: Neurodegeneration in Alzheimer's disease (AD) is characterized by pathological protein aggregates and inadequate activation of cell cycle regulating proteins. Recently, Smad proteins were identified to control the expression of AD relevant proteins such as APP, CDK4 and CDK inhibitors, both critical regulators of cell cycle activation. This might indicate a central role for Smads in AD pathology where they show a substantial deficiency and disturbed subcellular distribution in neurons. Still, the mechanisms driving relocation and decrease of neuronal Smad in AD are not well understood. However, Pin1, a peptidyl-prolyl-cis/trans-isomerase, which allows isomerization of tau protein, was recently identified also controlling the fate of Smads. Here we analyse a possible role of Pin1 for Smad disturbances in AD.
    Neuropathology and Applied Neurobiology 06/2014; 40(7). DOI:10.1111/nan.12163 · 4.97 Impact Factor
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    ABSTRACT: Humanized tumor mice (HTM) were generated by the co-transplantation of human hematopoietic stem cells and human breast cancer cells overexpressing HER2 into neonatal NOD-scid IL2Rγ(null) (NSG) mice. These mice are characterized by the development of a human immune system in combination with human breast cancer growth. Due to concurrent transplantation into newborn mice, transfer of MHC-mismatched tumor cells resulted in solid coexistence and immune cell activation (CD4(+) T cells, natural killer cells, and myeloid cells), but without evidence for rejection. Histological staining of the spleen of HTM revealed co-localization of human antigen-presenting cells together with human T and B cells allowing MHC-dependent interaction, and thereby the generation of T cell-dependent antibody production. Here, we investigated the capability of these mice to generate human tumor-specific antibodies and correlated immunoglobulin titers with tumor outgrowth. We found detectable IgM and also IgG amounts in the serum of HTM, which apparently controlled tumor development when IgG serum concentrations were above 10 µg/ml. Western blot analyses revealed that the tumor-specific antibodies generated in HTM did not recognize HER2/neu antigens, but different, possibly relevant antigens for breast cancer therapy. In conclusion, HTM offer a novel approach to generate complete human monoclonal antibodies that do not require further genetic manipulation (e. g., humanization) for a potential application in humans. In addition, efficacy and safety of the generated antibodies can be tested in the same mouse model under human-like conditions. This might be of particular interest for cancer subtypes with no currently available antibody therapy.
    mAbs 05/2014; 6(4). DOI:10.4161/mabs.29111 · 4.73 Impact Factor
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which mediates toxic responses to environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Besides its well known role in induction of xenobiotic metabolizing enzymes, for instance CYP1A1, the AhR is also involved in tumour promotion in rodents although the underlying mechanisms are still poorly understood. Additionally, the AhR is known to regulate cellular proliferation, which might result in either inhibition or stimulation of proliferation depending on the cell-type studied. Potential targets in hepatocarcinogenesis are liver oval (stem/progenitor) cells. In the present work we analysed the effect of TCDD on proliferation in oval cells derived from mouse liver. We show that TCDD inhibits proliferation in these cells. In line, the amount of G0/G1 cells increases in response to TCDD. We further show that the expression of cyclin D1 and cyclin A is decreased, while p27 is increased. As a result, the retinoblastoma protein is not phosphorylated thereby inducing G0/G1 arrest. Pharmacological inhibition of the AhR and knock-down of AhR expression by RNA interference decreased the inhibitory effect on cell cycle and protein expression, indicating that the AhR at least partially mediates cell cycle arrest.
    Toxicology Letters 09/2013; 223(1). DOI:10.1016/j.toxlet.2013.08.022 · 3.36 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2013; 51(01). DOI:10.1055/s-0032-1331905 · 1.67 Impact Factor
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    ABSTRACT: Label-free methods streamline quantitative proteomics of tissues by alleviating the need for metabolic labeling of proteins with stable isotopes. Here we detail and implement solutions to common problems in label-free data processing geared toward tissue proteomics by one-dimensional gel electrophoresis followed by liquid chromatography tandem mass spectrometry (geLC MS/MS). Our quantification pipeline showed high levels of performance in terms of duplicate reproducibility, linear dynamic range, and number of proteins identified and quantified. When applied to the liver of an adenomatous polyposis coli (APC) knockout mouse, we demonstrated an 8-fold increase in the number of statistically significant changing proteins compared to alternative approaches, including many more previously unidentified hydrophobic proteins. Better proteome coverage and quantification accuracy revealed molecular details of the perturbed energy metabolism.
    Journal of Proteome Research 06/2012; 11(7):3680-9. DOI:10.1021/pr300147z · 5.00 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by deregulation of neuronal cell cycle and differentiation control eventually resulting in cell death. During brain development, neuronal differentiation is regulated by Smad proteins, which are elements of the canonical transforming growth factor β (TGF-β) signaling pathway, linking receptor activation to gene expression. In the normal adult brain, Smad proteins are constitutively phosphorylated and predominantly localized in neuronal nuclei. Under neurodegenerative conditions such as AD, the subcellular localization of their phosphorylated forms is heavily disturbed, raising the question of whether a nuclear Smad deficiency in neurons might contribute to a loss of neuronal differentiation control and subsequent cell cycle re-entry. Here, we show by luciferase reporter assays, electromobility shift, and RNA interference (RNAi) technique a direct binding of Smad proteins to the CDK4 promoter inducing transcriptional inhibition of cell cycle-dependent kinase 4 (Cdk4). Mimicking the neuronal deficiency of Smad proteins observed in AD in cell culture by RNAi results in elevation of Cdk4 and retardation of neurite outgrowth. The results identify Smad proteins as direct transcriptional regulators of Cdk4 and add further evidence to a Smad-dependent deregulation of Cdk4 in AD, giving rise to neuronal dedifferentiation and cell death.
    Neurobiology of aging 03/2012; 33(12):2827-40. DOI:10.1016/j.neurobiolaging.2012.01.013 · 4.85 Impact Factor
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    ABSTRACT: Proliferation of oval cells, the bipotent precursor cells of the liver, requires impeded proliferation and loss of hepatocytes as well as a specific micro-environment, provided by adjacent sinusoidal cells of liver. Despite their immense importance for triggering the oval cell response, cells of hepatic sinusoids are rarely investigated. To elucidate the response of sinusoidal liver cells we have employed a choline-deficient, ethionine-supplemented (CDE) diet, a common method for inducing an oval cell response in rodent liver. We have utilised selected expression markers commonly used in the past for phenotypic discrimination of oval cells and sinusoidal cells: cytokeratin, E-cadherin and M2-pyruvate kinase for oval cells; and glial fibrillary acidic protein (GFAP) was used for hepatic stellate cells (HSCs). CDE diet leads to an activation of all cells of the hepatic sinusoid in the mouse liver. Beside oval cells, also HSCs and Kupffer cells proliferate. The entire fraction of proliferating cells in mouse liver as well as endothelial cells and cholangiocytes express M2-pyruvate kinase. Concomitantly, GFAP, long considered a unique marker of quiescent HSCs was upregulated in activated HSCs and expressed also in cholangiocytes and oval cells. Our results point to an important role of all types of sinusoidal cells in regeneration from CDE induced liver damage and call for utmost caution in using traditional marker for identifying specific cell types. Thus, M2-pyruvate kinase should no longer be used for estimating the oval cell response in mouse liver. CDE diet leads to activation of GFAP positive HSCs in the pericentral zone of liver lobulus. In the periportal zone the detection of GFAP in biliary cells and oval cells, calls other cell types as progenitors of hepatocytes into question under CDE diet conditions.
    Comparative Hepatology 10/2010; 9(1):8. DOI:10.1186/1476-5926-9-8 · 1.88 Impact Factor
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    ABSTRACT: Adverse alcohol effects in the liver involve oxidative metabolism, fat deposition and release of fibrogenic mediators, including TGF-beta. The work presents an assessment of liver damaging cross-talk between ethanol and TGF-beta in hepatocytes. To investigate TGF-beta effects on hepatocytes, microarray analyses were performed and validated by qRT-PCR, Western blot analysis and immunohistochemistry. The cellular state was determined by assessing lactate dehydrogenase, cellular glutathione, reactive oxygen species, lipid peroxidation and neutral lipid deposition. RNA interference was used for gene silencing in vitro. TGF-beta is induced in mouse livers after chronic ethanol insult, enhances ethanol induced oxidative stress and toxicity towards cultured hepatocytes plus induces lipid-, oxidative stress metabolism- and fibrogenesis-gene expression signatures. Interestingly, TGF-beta down-regulates alcohol metabolizing enzyme Adh1 mRNA in cultured hepatocytes and liver tissue from TGF-beta transgenic mice via the ALK5/Smad2/3 signalling branch, with Smad7 as a potent negative regulator. ADH1 deficiency is a determining factor for the increased lipid accumulation and Cyp2E1 dependent toxicity in liver cells upon alcohol challenge. Further, ADH1 expression was decreased during liver damage in an intragastric ethanol infusion mouse model. In the presence of ethanol, TGF-beta displays pro-steatotic action in hepatocytes via decreasing ADH1 expression. Low ADH1 levels are correlated with enhanced hepatocyte damage upon chronic alcohol consumption by favoring secondary metabolic pathways.
    Journal of Hepatology 03/2010; 52(3):407-16. DOI:10.1016/j.jhep.2009.12.003 · 10.40 Impact Factor
  • C Göhler · J Böttger · R Gebhardt · E Ueberham
    Zeitschrift für Gastroenterologie 01/2010; 48(01). DOI:10.1055/s-0029-1246405 · 1.67 Impact Factor
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    ABSTRACT: Smad2 and Smad3 are central molecules of the TGFbeta and activin receptor complex mediated intracellular signaling pathway. They function as important transcription factors playing essential roles in brain development. Interestingly they are also known to be involved in the pathogenesis of various neurological disorders (including Alzheimer's disease). Due to structural differences in the N-terminal Mad homology domain 1, Smad2 and Smad3 differ in their ability to bind DNA directly. A splice form of Smad2 lacking exon3, Smad2(Deltaexon3), assumes features of Smad3, in that it can directly bind to DNA resulting in a functional hybrid of Smad2 and Smad3 properties. There is very little information available on the expression of Smad2 isoforms in the brain. We report here that Smad2(Deltaexon3) is the most abundant of the two Smad2 isoforms in mouse brain and that Smad expression pattern alters during development and aging. Neuronal expression of Smad2(Deltaexon3) was confirmed by a single-cell PCR approach. Moreover, Smad2(Deltaexon3) predominates in the nuclear fraction of neurons, suggesting special function during brain differentiation. Our data indicate that there may be a specific role for Smad2(Deltaexon3) in neurons.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 05/2009; 27(5):501-10. DOI:10.1016/j.ijdevneu.2009.04.001 · 2.92 Impact Factor
  • E Ueberham · U Ueberham · J Grosche · J Böttger · R Gebhardt
    Zeitschrift für Gastroenterologie 01/2009; 47(01). DOI:10.1055/s-0029-1191806 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2009; 47(01). DOI:10.1055/s-0029-1191805 · 1.67 Impact Factor
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    ABSTRACT: The profibrogenic role of transforming growth factor (TGF)-beta in liver has mostly been attributed to hepatic stellate cell activation and excess matrix synthesis. Hepatocytes are believed to contribute to increased rates of apoptosis. Primary hepatocyte outgrowths and AML12 cells were used as an in vitro model to detect TGF-beta effects on the cellular phenotype and expression profile. Furthermore, a transgenic mouse model was used to determine the outcome of hepatocyte-specific Smad7 expression on fibrogenesis following CCl(4)-dependent damage. Samples from patients with chronic liver diseases were assessed for (partial) epithelial-to-mesenchymal transition (EMT) in hepatocytes. In primary cell cultures and in vivo, the majority of hepatocytes survive despite activated TGF-beta signaling. These cells display phenotypic changes and express proteins characteristic for (partial) EMT and fibrogenesis. Experimental expression of Smad7 in hepatocytes of mice attenuated TGF-beta signaling and EMT, resulted in less accumulation of interstitial collagens, and improved CCl(4)-provoked liver damage and fibrosis scores compared with controls. The data indicate that hepatocytes undergo TGF-beta-dependent EMT-like phenotypic changes and actively participate in fibrogenesis. Furthermore, ablation of TGF-beta signaling specifically in this cell type is sufficient to blunt the fibrogenic response.
    Gastroenterology 05/2008; 135(2):642-59. DOI:10.1053/j.gastro.2008.04.038 · 13.93 Impact Factor
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    ABSTRACT: Terminal differentiation requires molecules also involved in aging such as the cell cycle inhibitor p16(INK4a). Like other organs, the adult liver represents a quiescent organ with terminal differentiated cells, hepatocytes and cholangiocytes. These cells retain the ability to proliferate in response to liver injury or reduction of liver mass. However, under conditions which prevent mitotic activation of hepatocytes, regeneration can occur instead from facultative hepatic stem cells.For therapeutic application a non-toxic activation of this stem cell compartment is required. We have established transgenic mice with conditional overexpression of the cell cycle inhibitor p16(INK4a) in hepatocytes and have provoked and examined oval cell activation in adult liver in response to a range of proliferative stimuli. We could show that the liver specific expression of p16(INK4a) leads to a faster differentiation of hepatocytes and an activation of oval cells already in postnatal mice without negative consequences on liver function.
    Journal of Cellular and Molecular Medicine 04/2008; 12(2):622-38. DOI:10.1111/j.1582-4934.2007.00178.x · 3.70 Impact Factor
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    ABSTRACT: Liver fibrogenesis is a process involving a complex interaction of cellular components. We recently described a new role for hepatocytes in the process of fibrogenesis, in which TGF-β induces expression and secretion of CTGF, another potent profibrogenic cytokine. Interleukin-15 has emerged as a new player in several models of liver damage, but its precise role has not yet been determined. Real Time PCR showed that TGF-β induces IL-15 mRNA up to 80 fold in primary mouse hepatocytes, and up to 10 fold in AML12 cells. Using chemical inhibitors, we determined that, although ALK-5 activity is essential, ERK and JNK pathways cooperate in this induction. Two IL-15 isoforms are described, differing in the length of the signal peptide an we observed induction of both splice variants in mouse hepatocytes. Using siRNA, we determined that Smad3 but not Smad2 is necessary for ALK-5/Smad mediated IL-15 mRNA induction. Software analysis of a -1.8 kb region of the mouse IL-15 promoter revealed binding sites for Smad3, Fast-1 and AP-1, highlighting the potential cooperation between Smad and AP-1 complexes. By ELISA, we detected IL-15 in cell pellets but not in supernatants, indicating that IL-15 and the IL-15/IL-15 receptor complex are not secreted. Immunohistochemistry revealed induction of IL-15 in hepatocytes of TGF-β transgenic mice and patients with chronic liver disease due to HBV, Schistosomiasis and cholestasis. Our results indicate that IL-15 is induced in hepatocytes by TGF-β. We are currently investigating the biological significance of this finding.
    Zeitschrift für Gastroenterologie 01/2008; · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2008; 46(01). DOI:10.1055/s-2008-1037471 · 1.67 Impact Factor
  • Elke Ueberham · Thomas Aigner · Uwe Ueberham · Rolf Gebhardt
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    ABSTRACT: Oval cells are liver-specific bipotent stem cells which accumulate in injured liver when proliferation of mature hepatocytes and/or cholangiocytes is impaired. They represent an intermediary cell type with phenotypical characteristics of both, hepatocytes and cholangiocytes. Oval cells express specific cell surface proteins allowing their identification in situ. Most of these cell surface proteins, however, are recognized by antibodies in mouse liver tissue that are not commercially available or work only on frozen sections. We show herein the unequivocal identification of oval cells in paraffin-embedded mouse liver samples based on strong E-cadherin expression different from that of hepatocytes and bile duct cells. By comparing the pattern of E-cadherin expression with that of both, A6-antigen and CD44, we suggest a tight control of E-cadherin expression depending on the differentiation stage of the progenitor cells. In human cirrhotic liver samples E-cadherin expression was found as a common feature of both, typical and atypical reactions, and, thus, can also serve as an indication of the progenitor cell compartment activation.
    Journal of Molecular Histology 09/2007; 38(4):359-68. DOI:10.1007/s10735-007-9098-1 · 1.98 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2007; 45(08). DOI:10.1055/s-2007-988112 · 1.67 Impact Factor

Publication Stats

504 Citations
138.11 Total Impact Points


  • 2003–2014
    • University of Leipzig
      • • Institute of Biochemistry
      • • Interdisciplinary Centre for Clinical Research
      Leipzig, Saxony, Germany
  • 2010
    • Paul-Flechsig-Institut für Hirnforschung
      Leipzig, Saxony, Germany