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|Title:||Development of a Mechanistically-based Genetically Engineered PC12 Cell System to Detect p53-mediated cytotoxicity|
|Authors:||VAN VLIET ERWIN; ESKES CHANTRA; STINGELE Silvia; GARTLON JOANNE; FARINA MASSIMO; PONTI JESSICA; PRICE ANNA; SABBIONI ENRICO; HARTUNG THOMAS; COECKE SANDRA|
|Citation:||TOXICOLOGY IN VITRO vol. 21 no. 4 p. 698-705|
|Publisher:||PERGAMON-ELSEVIER SCIENCE LTD|
|JRC Publication N°:||JRC37498|
|Type:||Articles in Journals|
|Abstract:||The human wild type p53 gene, key for apoptosis, was introduced into the pheochromocytoma (PC12) cell line, to create a mechanistically-based in vitro test model for the detection of p53-mediated toxicity. Expression of the wt p53 gene was regulated by a system, which allowed or blocked expression p53 by absence or presence of tetracycline in the culture media. Western blot analyses confirmed an inducible and tetracycline-dependent expression of the wt p53 protein. Functionality of the p53 protein was verified by camptothecin treatment, known to induce p53-dependent apoptosis. Results showed that p53-expressing cells were significantly more sensitive to camptothecin induced cytotoxicity compared to non-expressing cells, and presented a significantly higher incidence of apoptosis. A screening study on 31 metal compounds, showed that the classified human carcinogens (NaAsO(2), CdSO(4).8H(2)O, Na(2)CrO(4).4H(2)O, MnCl(2), (NH(4))(2)PtCl(6)) significantly increased cytotoxicity in p53-expressing cells compared to non-expressing cells, suggesting that their cytotoxicity was p53-mediated. Finally, acute and subchronic treatment with methyl mercury showed no significant differences in cytotoxicity and the percentage of apoptosis or necrosis between p53-expressing and non-expressing differentiated cells, suggesting that methyl mercury cytotoxicity was p53-independent.|
|JRC Institute:||Institute for Health and Consumer Protection|
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