| Autor: |
Lambert, J. M. R., Moshfegh, A., Hainaut, P., Wiman, K. G., Bykov, V. J. N. |
| Předmět: |
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| Zdroj: |
Oncogene; 3/4/2010, Vol. 29 Issue 9, p1329-1338, 10p, 1 Color Photograph, 1 Diagram, 2 Charts, 2 Graphs |
| Abstrakt: |
The low molecular weight compound PRIMA-1MET reactivates mutant p53 and triggers mutant p53-dependent apoptosis in human tumor cells. We investigated the effect of PRIMA-1MET on global gene expression using microarray analysis of Saos-2 cells expressing His273 mutant p53 and parental p53 null Saos-2 cells. PRIMA-1MET affected transcription of a significantly larger number of genes in the mutant p53-expressing cells compared to the p53 null cells. Genes affected by PRIMA-1MET in a mutant p53-dependent manner include the cell-cycle regulators GADD45B and 14-3-3γ and the pro-apoptotic Noxa. Several of the affected genes are known p53 target genes and/or contain p53 DNA-binding motifs. We also found mutant p53-dependent disruption of the cytoskeleton, as well as transcriptional activation of the XBP1 gene and cleavage of its mRNA, a marker for endoplasmic reticulum stress. Our data show that PRIMA-1MET induces apoptosis through multiple transcription-dependent and -independent pathways. Such integral engagement of multiple pathways leading to apoptosis is consistent with restoration of wild-type properties to mutant p53 and is likely to reduce the risk of drug resistance development in clinical applications of PRIMA-1MET. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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