Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression

Abstract

The temporal gene expression profile during the entire process of apoptosis and cell cycle progression in response to p53 in human ovarian cancer cells was explored with cDNA microarrays representing 33 615 individual human genes. A total of 1501 genes (4.4%) were found to respond to p53 (approximately 80% of these were repressed by p53) using 2.5-fold change as a cutoff. It was anticipated that most of p53 responsive genes resulted from the secondary effect of p53 expression at late stage of apoptosis. To delineate potential p53 direct and indirect target genes during the process of apoptosis and cell cycle progression, microarray data were combined with global p53 DNA-binding site analysis. Here we showed that 361 out of 1501 p53 responsive genes contained p53 consensus DNA-binding sequence(s) in their regulatory region, approximately 80% of which were repressed by p53. This is the first time that a large number of p53-repressed genes have been identified to contain p53 consensus DNAbinding sequence(s) in their regulatory region. Hierarchical cluster analysis of these genes revealed distinct temporal expression patterns of transcriptional activation and repression by p53. More genes were activated at early time points, while more repressed genes were found after the onset of apoptosis. A small-scale quantitative chromatin immunoprecipitation analysis indicated that in vivo p53-DNA interaction was detected in eight out of 10 genes, most of which were repressed by p53 at the early onset of apoptosis, suggesting that a portion of p53 target genes in the human genome could be negatively regulated by p53 via sequence-specific DNA binding. The approaches and genes described here should aid the understanding of global gene regulatory network of p53.

A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells

“…25,26 Nevertheless, inhibition of EMMPRIN expression by p53 appears to be independent of transcriptional regulation, as we did not observe any effect of p53 on the expression of EMMPRIN mRNA (Fig. 3).…”

Transcriptional regulation by p53: one protein, many possibilities

“…Indeed, in addition to identification of multiple targets that are activated by p53, expression arrays have indicated that significant numbers of genes are downregulated after induction of p53 in many cases. [107][108][109][110] The molecular background of negative regulation of gene expression by p53 seems to be more diverse. Interestingly, earlier reports have suggested that transcriptional repression by p53 is the key activity that is required for its ability to induce cell death.…”

Identification of Primary Transcriptional Regulation of Cell Cycle-Regulated Genes upon DNA Damage

“…p53 has been reported to play an important role in trans-repression of cell-cycle-regulatory genes. 35,37,38 Well-known p53-responsive genes include CDC2, CCNB1, and TOP2a. [39][40][41] Despite the transcription factors E2F and NF-Y being enriched in both groups, cell cycle-dependent element (CDE) was significantly enriched in the target group and upstream stimulating factor (USF) was enriched in the non-target group.…”