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| 001 | 119266 | ||
| 005 | 20240228145430.0 | ||
| 024 | 7 | _ | |2 doi |a 10.1002/ijc.30504 |
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| 024 | 7 | _ | |2 pmc |a pmc:PMC5215675 |
| 024 | 7 | _ | |2 ISSN |a 0020-7136 |
| 024 | 7 | _ | |2 ISSN |a 1097-0215 |
| 037 | _ | _ | |a DKFZ-2017-00052 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |0 http://orcid.org/0000-0002-0341-4490 |a Kucab, Jill E |b 0 |
| 245 | _ | _ | |a Nutlin-3a selects for cells harbouring TP53 mutations. |
| 260 | _ | _ | |a Bognor Regis |b Wiley-Liss |c 2017 |
| 336 | 7 | _ | |2 DRIVER |a article |
| 336 | 7 | _ | |2 DataCite |a Output Types/Journal article |
| 336 | 7 | _ | |0 PUB:(DE-HGF)16 |2 PUB:(DE-HGF) |a Journal Article |b journal |m journal |s 1511333444_28942 |
| 336 | 7 | _ | |2 BibTeX |a ARTICLE |
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| 520 | _ | _ | |a TP53 mutations occur in half of all human tumours. Mutagen-induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock-in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen-treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2-5 months) and much effort is expended maintaining TP53-WT cultures. In order to improve the selectivity of the HIMA for HUFs harbouring TP53 mutations, we explored the use of Nutlin-3a, an MDM2 inhibitor that leads to stabilisation and activation of wild-type (WT) p53. First, we treated previously established immortal HUF lines carrying WT or mutated TP53 with Nutlin-3a to examine the effect on cell growth and p53 activation. Nutlin-3a induced the p53 pathway in TP53-WT HUFs and inhibited cell growth, whereas most TP53-mutated HUFs were resistant to Nutlin-3a. We then assessed whether Nutlin-3a treatment could discriminate between TP53-WT and TP53-mutated cells during the HIMA (n = 72 cultures). As immortal clones emerged from senescent cultures, each was treated with 10 µM Nutlin-3a for 5 days and observed for sensitivity or resistance. TP53 was subsequently sequenced from all immortalised clones. We found that all Nutlin-3a-resistant clones harboured TP53 mutations, which were diverse in position and functional impact, while all but one of the Nutlin-3a-sensitive clones were TP53-WT. These data suggest that including a Nutlin-3a counter-screen significantly improves the specificity and efficiency of the HIMA, whereby TP53-mutated clones are selected prior to sequencing and TP53-WT clones can be discarded. |
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| 700 | 1 | _ | |0 P:(DE-He78)f3bec70c95e9e3dce0f39d54b3843118 |a Hollstein, Monica |b 1 |u dkfz |
| 700 | 1 | _ | |a Arlt, Volker M |b 2 |
| 700 | 1 | _ | |a Phillips, David H |b 3 |
| 773 | _ | _ | |0 PERI:(DE-600)1474822-8 |a 10.1002/ijc.30504 |g Vol. 140, no. 4, p. 877 - 887 |n 4 |p 877 - 887 |t International journal of cancer |v 140 |x 0020-7136 |y 2017 |
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