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.
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.
Ceballos
Eva
E
Departamento de Biología Molecular y Unidad de Biomedicina-CSIC, Grupo de Biología Molecular del Cáncer, Facultad de Medicina, University of Cantabria, Santander 39011, Spain.
Muñoz-Alonso
Maria J
MJ
Berwanger
Bernd
B
Acosta
Juan C
JC
Hernández
Rafael
R
Krause
Michael
M
Hartmann
Oliver
O
Eilers
Martin
M
León
Javier
J
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D016259:Genes, myc; D006801:Humans; D020014:K562 Cells; D046228:Microarray Analysis; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D018832:Molecular Chaperones; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53