0000000000011260
AUTHOR
Sandra M. Schneider
TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A.
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 …
TCDD induces c-jun expression via a novel Ah (dioxin) receptor-mediated p38–MAPK-dependent pathway
The aryl hydrocarbon receptor (AhR) has a fundamental role during postnatal liver development and is essential for mediating dioxin toxicity. However, the genetic programs mediating, both, the toxic and physiological effects downstream of the transcription factor AhR are in major parts unknown. We have identified the proto-oncogene c-jun as a novel target gene of AhR. Induction of c-jun depends on activation of p38-mitogen-activated protein kinase (MAPK) by an AhR-dependent mechanism. None of the kinases that are known to phosphorylate p38-MAPK is activated by AhR. Neither the dephosphorylation rate of p38-MAPK is reduced. Furthermore, increased p38-MAPK phosphorylation in response to dioxi…
JNK phosphorylation relieves HDAC3-dependent suppression of the transcriptional activity of c-Jun
The AP-1 transcription factor c-Jun is a prototypical nuclear effector of the JNK signal transduction pathway. The integrity of JNK phosphorylation sites at serines 63/73 and at threonines 91/93 in c-Jun is essential for signal-dependent target gene activation. We show that c-Jun phosphorylation mediates dissociation of an inhibitory complex, which is associated with histone deacetylase 3 (HDAC3). The subsequent events that ultimately cause increased mRNA synthesis are independent of c-Jun phosphorylation and its interaction with JNK. These findings provide an 'activation by de-repression' model as an explanation for the stimulatory function of JNK on c-Jun.
Influence of aryl hydrocarbon- (Ah) receptor and genotoxins on DNA repair gene expression and cell survival of mouse hepatoma cells
The aryl hydrocarbon receptor (AhR) mediates toxicity of a variety of environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) and dioxins. However, the underlying mechanisms and genetic programmes regulated by AhR to cause adverse effects but also to counteract poisoning are still poorly understood. Here we analysed the effects of two AhR ligands, benzo[a]pyrene (B[a]P), a DNA damaging tumour initiator and promotor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a pure tumour promoter, on cell survival and on nucleotide excision repair (NER) gene expression. NER deals with so called "bulky" DNA adducts including those generated by enzymatically activated B[a]P. Therefore, t…