Dioxin-induced transcriptome and proteome alterations
Leader: Martin Göttlicher, Ulrich Andrae
Background
Carcinogenic chemicals can cause tumours by different mechanisms. Whereas certain compounds act primarily by inducing heritable genetic changes (mutations), others, the so-called „tumour promoters“, exert their effects predominantly via non-genotoxic mechanisms. For most of these tumour promoters their exact mode of action remains to be elucidated. The knowledge of the underlying mechanisms and the cellular signalling pathways affected would be expected to contribute to the identification of hitherto unknown aspects of the action of these agents and to yield novel insights into mechanisms of disease generation.
Our group deals with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or “dioxin”), a non-genotoxic, tumour-promoting chemical which is toxic at extremely low concentrations. The compound binds to a cytosolic target, the Ah or dioxin receptor. Following activation by dioxin, the receptor alters the expression of specific target genes. As a consequence of altered gene expression, other signalling pathways are modulated, which results in a disturbance of cell homeostasis, a broad range of toxic effects and, in the long run, tumour formation. The precise mechanisms responsible for the adverse health effects of dioxin are still largely unknown.
The focus of our work is on the analysis of the complex dioxin actions at the level of the transcriptome and the proteome. Particularly intriguing findings are pursued to clarify the underlying mechanisms and the importance for dioxin toxicity.
Our transcriptome analyses (Kolluri et al. 2001) have identified a number of novel dioxin-inducible genes, such as that of N-myristoyltransferase 2. N Myristoyltransferases modify proteins by replacing the amino acid methionine at the N-terminal end by the fatty acid myristic acid. Our present studies show that dioxin can induce the myristoylation of specific proteins. The functional consequences of the altered myristoylation are currently under investigation.
In two quantitative proteomic analyses using different methodological approaches (Sarioglu et al. 2006, 2008) we have identified over 150 proteins with altered abundance or posttranslational modifications in hepatic cells following dioxin exposure. The majority of these dioxin effects had not been known before. Amongst other things, the results indicate the importance of dioxin-induced oxidative stress for the activation of certain signalling pathways, e.g., the Keap/Nrf2 pathway, and they demonstrate a strong interference of dioxin with mitochondrial functions. The latter is exemplified by the observed up-regulation of the “voltage-dependent anion-selective channel protein 2“ (VDAC2), an antiapoptotic mitochondrial protein that regulates the activity of the proapoptotic protein BAK.