Showing papers by "Joerg Huelsken published in 2009"

Inducibility of Drug-Metabolizing Enzymes by Xenobiotics in Mice with Liver-Specific Knockout of Ctnnb1

Abstract: Basal as well as xenobiotic-induced expression of the main enzymes from phase I and phase II of drug metabolism is confined to the perivenous areas of the mammalian liver lobule. Whereas signal transduction pathways that govern xenobiotic-induced expression of these enzymes via ligand-activated transcription factors such as constitutive androstane receptor (CAR) or the aryl hydrocarbon receptor (AhR) have been intensively studied, the mechanisms regulating zone-specific basal expression of genes related to drug metabolism and preferential response of perivenous hepatocytes to xenobiotic inducers are still largely unknown. Recent publications by our and other groups point to an important role for the Wnt/β-catenin pathway in the maintenance of the perivenous hepatocyte gene expression profile including the main hepatic detoxification enzymes, and β-catenin signaling was recently implicated in the expression of several cytochrome P450 isoenzymes. To analyze, whether the β-catenin pathway would also affect inducible expression of drug-metabolizing enzymes, mice with liver-specific knockout of the Ctnnb1 gene (encoding β-catenin) were treated with different model inducers of xenobiotic metabolism. Knockout of β-catenin led to alterations in basal expression of most drug metabolism-related genes analyzed and resulted in strongly diminished responses to agonists of CAR-, AhR-, and nuclear factor erythroid-related factor 2-dependent transcription. Taken together, the data presented in this study indicate that β-catenin not only regulates basal expression of drug-metabolizing enzymes but also determines the magnitude and hepatic localization of response to xenobiotic inducers in vivo.

Cancer stem cells: never Wnt away from the niche.

Abstract: Purpose of review The last years of cancer research have established the concept of cancer stem cells (CSCs) as a subpopulation of cells within a tumor entirely responsible for tumorigenesis. This has aroused expectations that targeting cancer stem cells would allow effective tumor eradication. This review aims to summarize the relevant achievements in the field and to highlight the complex mechanisms that are involved in regulating CSC function. Recent findings A growing number of studies have identified CSCs in a variety of human tumor types. The focus of attention is now moving to discover molecular signals which are essential to sustain CSC. We summarize recent results on intrinsic and extrinsic signaling pathways such as Wnt signals, which control stem cell self-renewal and highlight the role of the microenvironment or niche in this process. Summary The discovery of cancer stem cells points into new directions to gain better understanding of cancer biology. This is expected to alter the design of clinical research programs and to improve the way we assess the efficacy of novel anticancer drugs. Several conclusions and predictions derived from this concept hold great promise to speed up the process of discovering effective targets for clinical application.

Canonical Wnt signalling plays essential roles.

Abstract: Keywords: Beta-Catenin ; Gamma-Catenin ; Hematopoiesis ; Lymphopoiesis Reference CDTSO-ARTICLE-2009-005doi:10.1002/eji.200838982View record in Web of Science Record created on 2009-12-17, modified on 2017-05-12

Tissue-specific stem cells: friend or foe?

Abstract: Keywords: Maintenance ; Catenin ; Marker ; Cancer ; Lgr5 Reference CDTSO-ARTICLE-2009-001doi:10.1038/cr.2009.24View record in Web of Science Record created on 2009-04-16, modified on 2017-05-12