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  • Original Paper
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Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

Abstract

We have previously demonstrated that c-Myc impairs p53-mediated apoptosis in K562 human leukemia cells, which lack ARF. To investigate the mechanisms by which c-Myc protects from p53-mediated apoptosis, we used K562 cells that conditionally express c-Myc and harbor a temperature-sensitive allele of p53. Gene expression profiles of cells expressing wild-type conformation p53 in the presence of either uninduced or induced c-Myc were analysed by cDNA microarrays. The results show that multiple p53 target genes are downregulated when c-Myc is present, including p21WAF1, MDM2, PERP, NOXA, GADD45, DDB2, PIR121 and p53R2. Also, a number of genes that are upregulated by c-Myc in cells expressing wild-type conformation p53 encode chaperones related to cell death protection as HSP105, HSP90 and HSP27. Both downregulation of p53 target genes and upregulation of chaperones could explain the inhibition of apoptosis observed in K562 cells with ectopic c-Myc. Myc-mediated impairment of p53 transactivation was not restricted to K562 cells, but it was reproduced in a panel of human cancer cell lines derived from different tissues. Our data suggest that elevated levels of Myc counteract p53 activity in human tumor cells that lack ARF. This mechanism could contribute to explain the c-Myc deregulation frequently found in cancer.

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Acknowledgements

We are grateful to Laura Attardi, Rainer Benndorf, Angel Corbí, Robert Eisenman, Tyler Jacks, Moshe Oren, Linda Penn, Manuel Serrano, Gustavo del Real, Tsukasa Shibue, Bert Vogelstein and Karen Vousden for cDNA clones, Patricio Aller, Nicholas Cowan for antibodies; Joan Massague, Xabier Mayol, Miguel Quintanilla, Joan Seoane, Augusto Silva and M Giulia Rizzo for cell lines; Pilar Frade and Rosa Blanco for technical assistance; and M Dolores Delgado for critical reading of the manuscript. The work was supported by grant SAF02-4193 from the Spanish Ministerio de Ciencia y Tecnología to JL and by the Deutsche Forschungsgemeinschaft and the Thyssen Stiftung to ME.

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Correspondence to Javier León.

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Ceballos, E., Muñoz-Alonso, M., Berwanger, B. et al. Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes. Oncogene 24, 4559–4571 (2005). https://doi.org/10.1038/sj.onc.1208652

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