A unique, short sequence determines p53 gene basal and UV-inducible expression in normal human cells.
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 X-ray 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 NFkappaB 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.
Noda
A
A
Department of Radiation Biophysics, Kobe University School of Medicine, 7-5-1 Kusunokicho, Chuo-ku, Kobe 650-0017, Japan.
Toma-Aiba
Y
Y
Fujiwara
Y
Y
D005786:Gene Expression Regulation / Q000528:radiation effects; D016158:Genes, p53; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000096:biosynthesis; D016385:TATA Box; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D014965:X-Rays
D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D012313:RNA