Research Projekts of the Research Group of Prof Schrenk
Biological responses mediated by the dioxin receptor
Inhibition of apoptosis as a mechanism of action of tumor promoters
Nutrition and colon healthiness
Biological responses mediated by the dioxin receptor
The dioxin- or Ah (aryl hydrocarbon) receptor (AhR) is a basic helix-loop-helix transcription factor, which is activated upon binding of ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). After subsequent binding of the aryl hydrocarbon receptor nuclear translocator (ARNT), the AhR complex binds to responsive elements in the 5'-flanking region of certain genes. Among these are primarily genes encoding drug-metabolizing enzymes such as cytochrome P4501A1 and 1A2, a UDP-glucuronosyltransferase, glutathione-S-transferase Ya and others. In addition, the genes encoding interleukin1ß and plasminogen activator inhibitor 2 (rat) are regulated via the AhR. Furthermore, binding of an agonist to the AhR results in direct activation of an AhR-associated tyrosine kinase (c-src).
TCDD, the most potent AhR agonist, is the prototype of the family of ›dioxins‹, and most of the toxic effects of TCDD and other ›dioxinlike‹ environmental pollutants are mediated by AhR activation. However, our knowledge on the down-stream mechanisms leading to toxicity are very limited.
Our group works on AhR-mediated induction of drug-metabolizing enzymes and on other biological effects of dioxins in tissue culture. Species comparions and investigations of the concentration-response relationships for various biochemical endpoints play a central role in these studies.
Inhibition of apoptosis as a mechanism of action of tumor promoters
Apoptosis (programmed cell death) can occur as a physiological process aimed at the scheduled elimination of cells which are no longer required. Furthermore, apoptosis represents a cellular response to severe and/or irreversible lesions of single cells e.g. by genotoxic damage. Interestingly, increased rates of apoptosis are freqeuntly observed in tumor cells and preneoplastic cells.
The inhibition of apoptosis of preneoplastic cells is probably a major mode of action of tumor promoters. The group of tumor promoters has in common that these agents are not genotoxic per se but facilitate or enhance the growth of preneoplastic cell clones. Thus exposure to tumor promoters can result in an earlier onset of malignant tumors or in a higher incidence of tumors at a certain time point. TCDD (see 1.) is one of the most potent tumor promoters in rodent liver. In humans, TCDD was classified as a carcinogen, underlining the outstanding importance of the further elucidation of the mechanisms of action of this class of promoters.
Our group utilizes in vitro and in vivo models in order to investigate the mechanisms of inhibition of apoptosis by liver tumor promoters such as TCDD. Changes in the phosphorylation pattern of key regulators of apoptosis are suspected to play a major role in this scenario.
Nutrition and colon healthiness
Colon tumors, i.e. the colorectal carcinoma are one of the most common cancers in developed countries. The mechanisms of cancer development include the induction of genetic alterations, but also life style factors are involved. The most important life style factors for developing colon cancers are dietary factors. Diets high in total fat and red meat are considered possibly causative. Conversely, diet related cancers are also considered to be preventable by high vegetable and fruit consumption.
The group of Prof. Schrenk is part of the nutrition network »Role of food ingredients in the development of intestinal diseases and potentiality of their prevention by nutrition«, which is financed by the german ministry of research and education and works on the investigation of apple components on the modulation of drug metabolizing enzymes in colon. A second interest lies in the investigation of apple components on the prevention of inflammatory bowel diseases. Preliminary results show that feeding apple juice to rats lead to a moderation of chemically triggered colonic inflammations.