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Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53

Oncogene volume 24, pages 3964–3975 (2005)Cite this article

Abstract

The aminothiol WR1065 exerts selective cytoprotective effects in normal cells compared to cancer cells and has clinical applications for the protection of normal cells in cancer patients undergoing radio- or chemotherapy. There is evidence that p53 is activated in response to WR1065. To examine the effects of WR1065 on the signalling pathways controlled by p53, isogeneic human colon carcinoma cell lines (HCT116) differing only in the presence or absence of wild-type p53 were used. Treatment with WR1065 resulted in G1 cell cycle arrest in the p53-positive cell line but not in the p53-negative cell line. Long-term exposure resulted in minimal apoptosis of either cell line. Changes in gene expression in p53-positive or -negative cells treated with WR1065 were examined using commercial human stress and cancer gene arrays (Clontech Atlas arrays). Genes found to be specifically upregulated in a p53-dependent manner included coproporphyrinogen oxidase, ICErel-II cysteine protease, macrophage inhibitory cytokine-1 (also known as placental transforming growth factor beta), S100A4, and Waf1/p21. However, most proapoptotic genes typically upregulated by p53 in response to DNA damage were not activated. These studies show that WR1065 specifically modulates a subset of p53 target genes in a colon carcinoma cell line, consistent with the observation that this agent elicits essentially p53-dependent, cell cycle arrest responses.

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Acknowledgements

We thank Jake Gray for his expert technical assistance in carrying out the Western blots of PTGFβ and Max Kullberg for his critical reading of the manuscript. K Mann was supported by the Biomedical Program at the University of Alaska and P Hainaut by European Community Grant QLG1-1999-00273 and Association pour la Recherche sur le Cancer (ARC) grant within the ARECA programme.

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  1. Department of Biological Sciences and Biomedical Program, University of Alaska, Anchorage, AK, 99508, USA

    Kristine Mann

  2. Group of Molecular Carcinogenesis, International Agency for Research on Cancer, 69372, Lyon, France

    Pierre Hainaut

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Correspondence to Kristine Mann.

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Mann, K., Hainaut, P. Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53. Oncogene 24, 3964–3975 (2005). https://doi.org/10.1038/sj.onc.1208563

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