Aminothiol wr1065 induces differential gene expression in the presence of wild-type p53

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. Access through your institution Buy or subscribe

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Cancer Ther._, 2, 1023–1029. Download references ACKNOWLEDGEMENTS We thank Jake Gray for his expert technical assistance in carrying out the Western blots of PTGF_β_ 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Biological Sciences and Biomedical Program, University of

Alaska, Anchorage, AK, 99508, USA Kristine Mann * Group of Molecular Carcinogenesis, International Agency for Research on Cancer, 69372, Lyon, France Pierre Hainaut Authors * Kristine Mann

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CORRESPONDING AUTHOR Correspondence to Kristine Mann. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 22 July 2004 * Revised:

21 December 2004 * Accepted: 10 January 2005 * Published: 07 March 2005 * Issue Date: 02 June 2005 * DOI: https://doi.org/10.1038/sj.onc.1208563 SHARE THIS ARTICLE Anyone you share the

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Nature SharedIt content-sharing initiative KEYWORDS * p53 * WR1065 * gene arrays * p21 * S100A4 * PTGF_β_