Pickles, JC;
Pant, K;
McGinty, LA;
Yasaei, H;
Roberts, T;
Scott, AD;
Newbold, RF;
(2016)
A mechanistic evaluation of the Syrian hamster embryo cell transformation assay (pH 6.7) and molecular events leading to senescence bypass in SHE cells.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis
, 802
pp. 50-58.
10.1016/j.mrgentox.2016.04.002.
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Pickles et al 2016 A mechanistic evaluation of the Syrian hamster embryo cell transformation assay (pH 6.7) and molecular events leading to senescence bypass in SHE cells.pdf Download (1MB) | Preview |
Abstract
The implementation of the Syrian hamster embryo cell transformation assay (SHE CTA) into test batteries and its relevance in predicting carcinogenicity has been long debated. Despite prevalidation studies to ensure reproducibility and minimise the subjective nature of the assay's endpoint, an underlying mechanistic and molecular basis supporting morphological transformation (MT) as an indicator of carcinogenesis is still missing. We found that only 20% of benzo(a)pyrene-induced MT clones immortalised suggesting that, alone, the MT phenotype is insufficient for senescence bypass. From a total of 12 B(a)P- immortalised MT lines, inactivating p53 mutations were identified in 30% of clones, and the majority of these were consistent with the potent carcinogen's mode of action. Expression of p16 was commonly silenced or markedly reduced with extensive promoter methylation observed in 45% of MT clones, while Bmi1 was strongly upregulated in 25% of clones. In instances where secondary events to MT appeared necessary for senescence bypass, as evidenced by a transient cellular crisis, clonal growth correlated with monoallelic deletion of the CDKN2A/B locus. The findings further implicate the importance of p16 and p53 pathways in regulating senescence while providing a molecular evaluation of SHE CTA -derived variant MT clones induced by benzo(a)pyrene.
| Type: | Article |
|---|---|
| Title: | A mechanistic evaluation of the Syrian hamster embryo cell transformation assay (pH 6.7) and molecular events leading to senescence bypass in SHE cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.mrgentox.2016.04.002 |
| Publisher version: | http://dx.doi.org/10.1016/j.mrgentox.2016.04.002 |
| Language: | English |
| Additional information: | Copyright © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the Creative Commons Attribution 4.0 International (CC BY 4.0) license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Cell transformation assay; Morphological transformation; Senescence bypass; Syrian hamster; p16/CDKN2A |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1497918 |
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