Die Rolle von p53 in der zellulären Antwort auf Natriumselenit und Selenomethionin [article]

Viola Klaus, Andrea Hartwig, Technische Universität Berlin, Technische Universität Berlin
The trace element selenium has been proposed to be cancer preventive, although results from epidemiological studies are inconsistent. Both antioxidative effects of certain selenoproteins, e.g. the glutathione peroxidase, as well as prooxidative effects such as the zinc release from metallothionein via oxidation of thiol groups have been suggested as underlying mechanism. Thus, an oxidative release of zinc from other zinc-binding proteins, e.g. transcription factors, DNA repair proteins or tumor
more » ... r proteins or tumor suppressors, could be possible. This would imply that proteins, which maintain the genomic integrity, could be damaged. In the present study the impact of sodium selenite and selenomethionine on the tumor suppressor protein p53 and p53-dependent cellular processes was investigated since the native conformation of p53 is stabilised by a zinc ion coordinated in the DNA-binding domain. In a subcellular test system the reducible sodium selenite provoked an unfolding of p53, which could be due to an oxidative zinc release. In comparison, the fully reduced selenomethionine had no effect. In a cellular context an unfolding of p53 would be expected to cause an inactivation of the transcription activity, regulating genes involved in DNA repair, cell cycle control and apoptosis. Thus, the impact of selenium compounds on these functions was determined by comparison of p53-proficient and p53-deficient HCT116 cells. It was shown that sodium selenite induced a p53-dependent cellular response. For example, the p53-proficient cells were more sensitive against sodium selenite than the p53-deficient cells. Moreover, sodium selenite provoked a p53-dependent G1 cell cycle arrest accompanied by the up-regulation of p21 gene expression. Similarly, p53 played a crucial role in the induction of apoptotic processes, e.g. the induction of Bax, the nuclear localisation of AIF or the fragmentation of DNA measured as SubG1-peak. Furthermore, in the p53-proficient cell line no accumulation of oxidative DNA damage could be detected up to cytotoxic conce [...]
doi:10.14279/depositonce-2576 fatcat:23lnlbre5zgp5jg47ehfppof6a