A unique, short sequence determines p53 gene basal and UV-inducible expression in normal human cells

Abstract

The p53 tumor suppressor protein plays a central role in the cellular defence against agents which cause genetic damage. The induction and activation of p53 upon stress has been shown at post-transcription level by multiple mechanisms, while the regulatory role of p53 gene transcription is still poorly understood. Here we show that the causative mechanisms underlying this activation are attributed in part to the promoter function of p53. In various normal human cells, p53 gene expression is induced transcriptionally by ultraviolet (UV) but not Xray irradiation. We determined that, by p53 promoter dissection, the 21 bp element (PE21) responsible for this UV activation resides adjacent to, and upstream to the putative NFkB binding site. Moreover, the PE21 sequence was found to be a primary determinant for human p53 gene basal expression carrying bi-directional transcriptional initiation activity, which controls the initiation of RNA synthesis about 50 bases downstream, indicating that the sequence plays a critical role in both basal and inducible transcription. Finally, we detected the putative PE21 binding factor(s) in nuclear extracts from non-irradiated and irradiated cells. Since the PE21 sequence does not show any homologies to the conventional TATA or GC box, or to an`initiatior', all of which determine the initiation site for transcription, the PE21 sequence appears to be a new class in eukaryotic promoter elements. Our results indicate that the mechanism of PE21-directed p53 mRNA transcription has an important role in the cellular stress response as well as tumor suppression. Oncogene (2000) 19, 21 ± 31.

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

“…Importantly, the expression levels of p53 in all the MCF7 samples were much higher than that in the HeLa samples analyzed. Consistent with previous results (Noda et al, 2000), UV treatment significantly increased accumulation of p53 and this was not affected by control siRNAs (Figure 2d). The depletion of p53 in HeLa cells abolished the UV-induced inhibition of mRNA 3 0 end cleavage ( Figure 2b, compare lanes 4 and 6), indicating that p53 has an inhibitory effect on mRNA 3 0 cleavage under DNA-damaging conditions.…”

Negative Regulation of Tumor Suppressor p53 Transcription in Breast Cancer Cells

“…This result is not totally surprising as the previous studies with UV-induction did not detect a different binding pattern with the PE21 sequence and nuclear extracts isolated from UV-irradiated and non irradiated fibroblasts (27). Our results combined with the prior study suggest that regulation of p53 transcription through the PE21 element by OM is mediated by mechanisms other than direct alteration of the DNA binding activity of the PE21 interacting proteins.…”

“…The PE21 element was originally discovered by searching for the sequence that was responsible for the UV-induced transcription of the p53 gene in human fibroblasts (27). Intriguingly, in this study, we found that the repressive effect of OM on p53 transcription was also mediated through this regulatory element.…”

Crosstalk between PARP-1 and NF-κB modulates the promotion of skin neoplasia

“…Recent work suggests the involvement of p53 promoter activation by NF-kB (Benoit et al, 2000) and the existence of a promoter element that is involved in basal p53 gene expression and the stress response (Noda et al, 2000). Thus, suppression of NF-kB in cancer cells may provide an additional target for prevention of cancer.…”