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Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo
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Sullivan, Alexandra, Syed, Nelofer, Gasco, Milena, Bergamaschi, Daniele, Trigiante, Giuseppe, Attard, Marlene, Hiller, Louise, Farrell, Paul J, Smith, Paul, Lu, Xin and Crook, Tim (2004) Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo. Oncogene, 23 (19). pp. 3328-3337. doi:10.1038/sj.onc.1207428 ISSN 0950-9232.
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Official URL: http://dx.doi.org/10.1038/sj.onc.1207428
Abstract
A single-nucleotide polymorphism (SNP) in exon 4 results in expression of either arginine (72R) or proline (72P) at codon 72 of p53. We demonstrate that the in vitro response of cells exposed to anticancer agents is strongly influenced by this SNP in wild-type p53. In inducible systems and in cells expressing the endogenous protein, expression of 72P wild-type p53 results in a predominant G1 arrest, with only a minor apoptosis, at drug concentrations causing extensive apoptosis in cells expressing the 72R wild-type variant. The superior apoptosis-inducing activity of the 72R form correlates with more efficient induction of specific apoptosis-associated genes, and is maximal in the presence of serine 46 (S46). In vivo, the outcome of chemo-radiotherapy of squamous carcinomas is more favourable in cancers retaining a wild-type 72R allele, such cases having higher response rates and longer survival than those with wild-type 72P. Together, these results reveal that this SNP is an important determinant of response to anticancer agents in cells expressing wild-type p53. Analysis of complete p53 genotype (mutation and SNP) merits detailed investigation as a simple means for prediction of treatment response and survival in clinical oncology.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | Oncogene | ||||||
| Publisher: | Springer Nature | ||||||
| ISSN: | 0950-9232 | ||||||
| Official Date: | 22 April 2004 | ||||||
| Dates: |
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| Volume: | 23 | ||||||
| Number: | 19 | ||||||
| Page Range: | pp. 3328-3337 | ||||||
| DOI: | 10.1038/sj.onc.1207428 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access |
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