Redox regulation of methylthioadenosine phosphorylase in liver cells: molecular mechanism and functional implications

MTAP (5'-methylthioadenosine phosphorylase) catalyses the reversible phosphorolytic cleavage of methylthioadenosine leading to the production of methylthioribose-1-phosphate and adenine. Deficient MTAP activity has been correlated with human diseases including cirrhosis and hepatocellular carcinoma. In the present study we have investigated the regulation of MTAP by ROS (reactive oxygen species). The results of the present study support the inactivation of MTAP in the liver of bacterial LPS (lipopolysaccharide)-challenged mice as well as in HepG2 cells after exposure to t-butyl hydroperoxide. Reversible inactivation of purified MTAP by hydrogen peroxide results from a reduction of V(max) and involves the specific oxidation of Cys(136) and Cys(223) thiols to sulfenic acid that may be further stabilized to sulfenyl amide intermediates. Additionally, we found that Cys(145) and Cys(211) were disulfide bonded upon hydrogen peroxide exposure. However, this modification is not relevant to the mediation of the loss of MTAP activity as assessed by site-directed mutagenesis. Regulation of MTAP by ROS might participate in the redox regulation of the methionine catabolic pathway in the liver. Reduced MTA (5'-deoxy-5'-methylthioadenosine)-degrading activity may compensate for the deficient production of the precursor S-adenosylmethionine, allowing maintenance of intracellular MTA levels that may be critical to ensure cellular adaptation to physiopathological conditions such as inflammation

Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells

Hepatocellular carcinoma is a major cause of cancer-related deaths. Current treatments are not effective, and the identification of relevant pathways and novel therapeutic targets are much needed. Increasing evidences point to the activation of the epidermal growth factor receptor (EGFR) as an important mechanism in the development of hepatocarcinoma. We previously described that amphiregulin (AR), a ligand of the EGFR, is not expressed in healthy liver but is up-regulated during chronic liver injury, the background on which most liver tumors develop. Now, we have studied the expression and role of AR in human hepatocarcinoma. AR expression and function was studied in human liver tumors and cell lines. AR is expressed in human hepatocellular carcinoma tissues and cell lines and behaves as a mitogenic and antiapoptotic growth factor for hepatocarcinoma cells. We provide several lines of evidence, including AR silencing by small interfering RNAs and inhibition of amphiregulin by neutralizing antibodies, showing the existence of an AR-mediated autocrine loop that contributes to the transformed phenotype. Indeed, interference with endogenous AR production resulted in reduced constitutive EGFR signaling, inhibition of cell proliferation, anchorage-independent growth, and enhanced apoptosis. Moreover, knockdown of AR potentiated transforming growth factor-beta and doxorubicin-induced apoptosis. Conversely, overexpression of AR in SK-Hep1 cells enhanced their proliferation rate, anchorage-independent growth, drug resistance, and in vivo tumorigenic potential. These observations suggest that AR is involved in the acquisition of neoplastic traits in the liver and thus constitutes a novel therapeutic target in human hepatocarcinoma

Novel role for amphiregulin in protection from liver injury

Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor alpha, heparin-binding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases

The epidermal growth factor receptor ligand amphiregulin is a negative regulator of hepatic acute-phase gene expression

BACKGROUND/AIMS: The modulation of the hepatic acute-phase reaction (APR) that occurs during inflammation and liver regeneration is important for allowing normal hepatocellular proliferation and the restoration of homeostasis. Activation of acute-phase protein (APP) gene expression by interleukin-6 (IL-6)-type cytokines is thought to be counteracted by growth factors released during hepatic inflammation and regeneration. The epidermal growth factor receptor (EGFR) ligand amphiregulin (AR) is readily induced by inflammatory signals and plays a nonredundant protective role during liver injury. In this paper, we investigated the role of AR as a modulator of liver APP gene expression. METHODS: Expression of APP genes was measured in the livers of AR(+/+) and AR(-/-)mice during inflammation and regeneration and in cultured liver cells treated with AR and oncostatin M (OSM). Crosstalk between AR and OSM signalling was studied. RESULTS: APP genes were overexpressed in the livers of AR(-/-) mice during inflammation and hepatocellular regeneration. In cultured AR-null hepatocytes and human hepatocellular carcinoma (HCC) cells after AR knockdown, APP gene expression is enhanced. AR counteracts OSM-triggered signal transducer and activator of transcription 3 signalling in hepatocytes and attenuates APP gene transcription. CONCLUSIONS: Our data support the relevance of EGFR-mediated signalling in the modulation of cytokine-activated pathways. We have identified AR as a key regulator of hepatic APP gene expression during inflammation and liver regeneration

Advances in Science No. 01

Esta publicación tiene la decidida intención de acercar la investigación que realiza la Universidad del Rosario de Bogotá, Colombia, a un gran número de lectores para mostrarles, desde el periodismo científico, el quehacer investigativo de la institución. Queremos presentarle al mundo, tal como lo dijo hace dos siglos uno de nuestros hijos más ilustres, Francisco José de Caldas, el sentido final del ejercicio de investigar: “[...] todo para bienestar de los hombres”.It is the explicit goal of this publication is to get research carried out by the Universidad del Rosario in Bogotá, Colombia to a large number of readers, showing them, through sci-ence journalism, the daily investigative work carried out at this institution. And we want the world to see it in the spirit of the ultimate meaning of the practice of research, just as it was expressed two centuries ago by one of our most illustrious sons, Francisco José de Caldas, who underlined that it is “all for the well-being of humankind.

cDf International Congress : proceedings : actes, actas : actes, Barcelona Jun. 2013

El Congrés Internacional coupDefouet Barcelona 2013 ha estat una iniciativa de l'Art Nouveau European Route – Ruta Europea del Modernisme, organitzada per l'Institut del Paisatge Urbà de l'Ajuntament de Barcelona i el grup de recerca GRACMON de la Universitat de BarcelonaCoordinació: Lluís Bosch, Mireia Freixa.[eng] In 2013 the magazine coupDefouet reached its first decade of existence. As a way of celebrating this, the Art Nouveau European Route – the association of cities and other local institutions for the promotion and diffusion of Art Nouveau heritage that created the magazine – organised a magnificent international congress as a framework for scientific exchange and raising public awareness. The first coupDefouet International Congress on Art Nouveau was held in Barcelona, the city from which coupDefouet is published and one of the undisputable world capitals of Art Nouveau. This volume of the Singularitats series comprises the proceedings of that event.[cat] L’any 2013 va fer deu anys de l’aparició de coupDefouet, la revista de la Ruta Europea del Modernisme, una associació de municipis i altres entitats locals per a la promoció i la difusió del patrimoni modernista o Art Nouveau. Per commemorar-ho, s’organitzà un congrés internacional amb l’objectiu de contribuir al coneixement científic i la difusió d’aquest moviment artístic. El primer Congrés Internacional coupDefouet se celebrà a Barcelona, la ciutat en què s’edita coupDefouet i una de les capitals indiscutibles de l’Art Nouveau. En aquest volum de Singularitats s’apleguen les actes d’aquell esdeveniment