Showing papers by "Franz Oesch published in 2008"

TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A.

Abstract: The aryl hydrocarbon receptor (AhR) is a transcription factor involved in physiological processes, but also mediates most, if not all, toxic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Activation of the AhR by TCDD leads to its dimerization with aryl hydrocarbon nuclear translocator (ARNT) and transcriptional activation of several phase I and II metabolizing enzymes. However, this classical signalling pathway so far failed to explain the pleiotropic hazardous effects of TCDD, such as developmental toxicity and tumour promotion. Thus, there is an urgent need to define genetic programmes orchestrated by AhR to unravel its role in physiology and toxicology. Here we show that TCDD treatment of rat liver oval cells leads to induction of the transcription factor JunD, resulting in transcriptional upregulation of the proto-oncogene cyclin A which finally triggers a release from contact inhibition. Ectopic expression of cyclin A in confluent cultures overcomes G1 arrest, indicating that increased cyclin A levels are indeed sufficient to bypass contact inhibition. Functional interference with AhR-, but not with ARNT, abolished TCDD-induced increase in JunD and cyclin A and prevented loss of contact inhibition. In summary, we have discovered a novel AhR-dependent and probably ARNT-independent signalling pathway involving JunD and cyclin A, which mediates TCDD-induced deregulation of cell cycle control.

New aspects on mechanisms of chemical carcinogenesis: emphasis on species and gender/sex differences and developmental/aging determinants.

Abstract: The workshop was organized on behalf of the European Network of Excellence (NoE) Environmental Cancer, Nutrition and Individual Susceptibility (ECNIS). ECNIS focuses on the utility of biomarkers relevant to assess environmental cancer risk. The most important components of the ECNIS science integration activities are scientiWc cooperations, intensive workshops focused on Environmental Cancer, Nutrition and Individual Susceptibility, various joint training and mobility programs including scientiWc meetings, exchange of researchers and shared laboratory facilities as well as joint training programs. An overall objective of ECNIS is to disseminate acquired knowledge to the scientiWc community as is intended with this Meeting Report. For further information on ECNIS see also http:// www.ecnis.org. A work package 10 “Mechanistic research to support cancer hazard and risk assessment” coordinated by Franz Oesch (University of Mainz, Germany) investigates the inXuence of various selected and still poorly understood determinants on mechanisms of carcinogenesis. Past eVorts gathered and revisited information on dose response relations in chemical carcinogenesis and the action of mixtures of carcinogens. In a recent workshop held in Debowa Gora, Poland on 24 April organized by Carsten Weiss (Research Centre Karlsruhe, Germany) and Franz Oesch together with Cornelia Dietrich and Barbara Oesch (University of Mainz, Germany) eVects of species and gender/sex diVerences as well as developmental and aging determinants in environmental cancer were presented and discussed. The multistep process of chemical carcinogenesis involves procarcinogen activation to a genotoxin and induction of mutations in critical genes, many of which favor the growth of initiated cells which, after clonal expansion, eventually give rise to a tumor. Cellular defense mechanisms counteract carcinogenesis at multiple levels e.g. carcinogen metabolism, DNA repair, cell cycle arrest and/or apoptosis (Hengstler et al. 2003). Although these individual steps have been studied intensely over the last decades there are major gaps in our knowledge on how for example species and gender/sex diVerences but also diVerent developmental stages decisively modulate these processes and, in turn, how development and aging is modulated by carcinogens. In a series of consecutive talks the workshop addressed novel aspects in environmental cancer. One focus was on Meeting report of the ECNIS workshop on basic mechanisms of carcinogenesis.

Dose-response and potential thresholds in tumour development.

Abstract: ECNIS is a Network of Excellence within the European Union’s Sixth Framework Programme, Priority 5: Food Quality and Safety. It brings together some of the best European research groups in a concerted effort to achieve improved understanding of the environmental causes of cancer, of the potential of diet to prevent cancer, and of the ways by which heredity can affect individual susceptibility to carcinogens, with the ultimate aim of reducing the cancer burden in Europe. ECNIS is coordinated by Prof. Konrad Rydzynski, The Nofer Institute of Occupational Medicine, Sw. Teresy 8, 91-348 ¸Lodz, Poland. This review has been prepared as part of ECNIS Work Package 10: Mechanistic research to support cancer hazard and risk assessment.