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 p21 WAF1 , 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.

Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway

“…Interestingly, the most potently downregulated gene following proteasome inhibition was the oncogenic transcription factor, c-myc, which may have a role in the antitumorigenic effect of PIs. Furthermore, c-myc has been shown to have an inhibitory effect on p53-dependent target gene expression and apoptosis (Ceballos et al, 2005).…”

CYFIP2, a Direct p53 Target, is Leptomycin-B Sensitive

“…These results are consistent with those from previously published microarray studies. 11,24,25 Saller et al first identified CYFIP2 (also known as PIR121) as a candidate p53 target gene whose mRNA was up regulated 5.3X by wild-type p53, 15.3X by a pro-apoptotic p53-121F mutant, and not induced in response to an anti-apoptotic p53-277R mutant, respectively, when stably expressed under TET control in H1299 cells or adenovirally expressed in Saos-2 (null for p53) or U2OS (expressing WT p53) cells. Using the nucleotide analog 5-fluorouracil, a DNA damage inducing chemotherapeutic drug, Kho et al detected a 2X increase in CYFIP2 mRNA by microarray in HCT116 cells in a p53-dependent manner, suggesting that CYFIP2 can be induced by endogenous p53.…”

Essential Dosage-Dependent Functions of the Transcription Factor Yin Yang 1 in Late Embryonic Development and Cell Cycle Progression

“…In both panels A and B, the YY1 and actin control RT-PCRs are shown in the right panels. (18,27,31,40,42,74), their deregulation upon depletion of YY1 mimicking the effects of p53 induction (see Table 2; see also Table S1 in the supplemental material). Taken together, these results raise the possibility that the cellular phenotype (i.e., cell cycle arrest) and changes in gene expression profiles induced by depletion of YY1 in mouse embryonic fibroblasts might be mediated, at least in part, via an increase in p53 expression and/or stability.…”

“…Reverse transcription was carried out with 2 g of total RNA (prepared as described above) using the Superscript III reverse transcriptase and oligo(dT) [12][13][14][15][16][17][18] primers (Invitrogen Life Technologies). Once the semiquantitative conditions were set up, equivalent amounts of yy1 ϩ/ϩ , yy1 f/f and yy1 flox/Ϫ RT products were submitted to amplification with various sets of PCR primers, and the PCR products were analyzed on ethidium bromidestained agarose gels.…”