Publications (13) View all
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Article: Caveolin and TGF-β entanglements.
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ABSTRACT: Transforming growth factor (TGF)-β is a multifunctional cytokine acting during development, tissue homeostasis, regeneration processes and disease progression. Due to its pleiotropic effects, tight regulation of the induced signaling cascades is mandatory. Caveolin proteins regulate a specific endocytic pathway and modulate diverse signaling pathways and thus have been related to severe disorders, e.g. cancer and fibrosis. Caveolin affects TGF-β/-Smad and non-Smad signaling in many ways and thus can determine the cellular outcome upon TGF-β challenge. Reciprocal regulation of caveolin and TGF-β is also evident, ranging from gene expression to miRNA regulation. Finally, there is in vivo evidence that this crosstalk influences disease development and progression. This review gives an overview about the multifaceted relations of caveolin and TGF-β. © 2013 Wiley Periodicals, Inc.Journal of Cellular Physiology 04/2013; · 3.87 Impact Factor -
Article: Distinct dedifferentiation processes affect caveolin-1 expression in hepatocytes.
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ABSTRACT: BACKGROUND: Dedifferentiation and loss of hepatocyte polarity during primary culture of hepatocytes are major drawbacks for metabolic analyses. As a prominent profibrotic cytokine and potent inducer of epithelial mesenchymal transition (EMT), TGF-beta contributes to these processes in liver epithelial cells. Yet, a distinction between culture dependent and TGF-beta driven hepatocyte dedifferentiation has not been shown to date. RESULTS: Here, we show that in both settings, mesenchymal markers are induced. However, upregulation of Snai1 and downregulation of E-Cadherin are restricted to TGF-beta effects, neglecting a full EMT of culture dependent hepatocyte dedifferentiation. Mechanistically, the latter is mediated via FAK/Src/ERK/AKT pathways leading to the induction of the oncogene caveolin-1 (Cav1). Cav1 was recently proposed as a new EMT marker, but our results demonstrate Cav1 is not up-regulated in TGF-beta mediated hepatocyte EMT, thus limiting validity of its use for this purpose. Importantly, marking differences on Cav1 expression exist in HCC cell lines. Whereas well differentiated HCC cell lines exhibit low and inducible Cav1 protein levels - by TGF-beta in a FAK/Src dependent manner, poorly differentiated cell lines display high Cav1 expression levels which are not further modulated by TGF-beta. CONCLUSIONS: This study draws a detailed distinction between intrinsic and TGF-beta mediated hepatocyte dedifferentiation and elucidates cellular pathways involved. Additionally, by evaluating the regulation of the oncogene Cav1, we provide evidence to argue against Cav1 as a reliable EMT marker.Cell Communication and Signaling 01/2013; 11(1):6. · 5.50 Impact Factor -
Article: Animal Models of Chronic Liver Diseases.
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ABSTRACT: Chronic liver diseases are frequent and potentially life threatening for humans. The underlying aetiologies are divers, ranging from viral infections, autoimmune disorders, intoxications (including alcohol abuse) to imbalanced diets. Although at early stage of disease the liver regenerates in the absence of the insult, advanced stages cannot be healed and may require organ transplantation. A better understanding of underlying mechanisms is mandatory for the design of new drugs to be used in clinic. Therefore, rodent models are being developed to mimic human liver disease. However, no model to date can completely recapitulate the "corresponding" human disorder. Limiting factors are the time frame required in humans to establish a certain liver disease, rodents possess a distinct immune system compared to humans and have different metabolic rates affecting liver homeostasis. These features account for the difficulties in developing adequate rodent models for studying disease progression and for testing new pharmaceuticals to be translated into the clinic. Nevertheless, traditional and new promising animal models that mimic certain attributes of chronic liver diseases are established and being used to deepen our understanding in the underlying mechanisms of distinct liver diseases. This review aims at providing a comprehensive overview of recent advances in animal models recapitulating different features and aetiologies of human liver diseases.AJP Gastrointestinal and Liver Physiology 12/2012; · 3.43 Impact Factor -
Article: Dynamics and feedback loops in the transforming growth factor β signaling pathway.
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ABSTRACT: Transforming growth factor β (TGF-β) ligands activate a signaling cascade with multiple cell context dependent outcomes. Disruption or disturbance leads to variant clinical disorders. To develop strategies for disease intervention, delineation of the pathway in further detail is required. Current theoretical models of this pathway describe production and degradation of signal mediating proteins and signal transduction from the cell surface into the nucleus, whereas feedback loops have not exhaustively been included. In this study we present a mathematical model to determine the relevance of feedback regulators (Arkadia, Smad7, Smurf1, Smurf2, SnoN and Ski) on TGF-β target gene expression and the potential to initiate stable oscillations within a realistic parameter space. We employed massive sampling of the parameters space to pinpoint crucial players for potential oscillations as well as transcriptional product levels. We identified Smad7 and Smurf2 with the highest impact on the dynamics. Based on these findings, we conducted preliminary time course experiments.Biophysical chemistry 03/2012; 162:22-34. · 2.28 Impact Factor -
Article: IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-β-independent Smad signaling.
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ABSTRACT: Connective tissue growth factor (CTGF) plays a central role in stimulating extracellular matrix deposition in the liver, and hence is considered a critical mediator of TGF-β-dependent fibrogenesis. Hepatic stellate cells (HSCs) are known as the major source of CTGF in damaged liver. However, previous studies revealed that IL-13, rather than TGF-β, represents the predominant inducer of CTGF expression in HSCs. We now dissected IL-13 downstream signaling that modulates CTGF expression in HSCs. IL-13 induces a time- and dosage-dependent increase of CTGF in a TGF-β-independent manner. This process requires participation of different Smad proteins and their upstream receptor kinases (activin receptor-like kinases). Smad1 and Smad2 were identified as the key mediators of IL-13-dependent CTGF expression. Furthermore, IL-13 induces Stat6 phosphorylation in HSCs, but Stat6 was not involved in CTGF induction. Instead, the Erk1/2-MAPK pathway was found to be responsible for IL-13-induced early Smad phosphorylation and CTGF synthesis. We demonstrate that IL-13 induces CTGF expression in HSCs by activating TGF-β-independent activin receptor-like kinase/Smad signaling via the Erk-MAPK pathway rather than via its canonical JAK/Stat6 pathway. These results provide an improved new insight into the molecular mechanisms of profibrotic IL-13 activities in the liver.The Journal of Immunology 09/2011; 187(5):2814-23. · 5.79 Impact Factor
