Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation

The cellular response to Nutlin-3, a small-molecule inhibitor of the p53 repressor MDM2, varies widely among human cancer-derived cell types. Whereas HCT116 colorectal carcinoma cells display sustained cell cycle arrest, BV173 leukemia cells undergo rapid apoptosis and other cell lines show an inter...

Full description

Saved in:
Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2008-08, Vol.7 (15), p.2427-2433
Main Authors: París, Ramiro, Henry, Ryan E., Stephens, Sarah J., McBryde, Meagan, Espinosa, Joaquín M.
Format: Article
Language:English
Subjects:
14-3-3 Proteins - genetics
Apoptosis - drug effects
Apoptosis - genetics
Binding
Biology
Bioscience
Calcium
Cancer
Carcinoma - genetics
Carcinoma - pathology
Cell
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Cycle
Cyclin-Dependent Kinase Inhibitor p21 - genetics
Gene Expression Regulation
Gene Silencing - physiology
HCT116 Cells
Humans
Imidazoles - pharmacology
Landes
MicroRNAs - physiology
Models, Biological
Organogenesis
Piperazines - pharmacology
Proteins
Signal Transduction - genetics
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Protein p53 - physiology
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The cellular response to Nutlin-3, a small-molecule inhibitor of the p53 repressor MDM2, varies widely among human cancer-derived cell types. Whereas HCT116 colorectal carcinoma cells display sustained cell cycle arrest, BV173 leukemia cells undergo rapid apoptosis and other cell lines show an intermediate response. We found that the expression of the p53 target genes p21, 14-3-3σ and the microRNA miR-34a correlates tightly with the cell fate choice adopted. All three genes were strongly induced in arresting cells, but silenced in cells undergoing Nutlin-3-induced apoptosis. In contrast, key apoptotic p53 target genes were equally expressed in arresting and apoptotic cells. Interestingly, we establish that miR-34a cooperates with p21 and 14-3-3σ to override the apoptotic signals generated by p53 activation. Strikingly, p53 binding to chromatin and p53-mediated recruitment of certain coactivators to all three target loci does not vary among cell types. Instead, the cell type-specific silencing of these genes is due to enhanced p21 mRNA degradation, 14-3-3σ promoter DNA methylation and reduced processing of the miR-34a primary transcript. Thus, p53-independent events regulating expression of protein-coding genes and microRNAs within the network can define the cellular outcome of p53 activation.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.6420