Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-kappaB and Myc/Max.
Transcriptional control of p53 expression participates in the generation of appropriate levels of active p53 in response to mitogenic stimulation. This prompted us to study the role of a putative AP-1 and a NF-kappaB motif in the human p53 promoter for transcriptional regulation. We show that mutation of the AP-1 or the NF-kappaB motif abolishes transcription from the human p53 promoter in HeLa, HepG2 and adenovirus type 5 E1-transformed 293 cells. In comparison, mutation of the previously characterized Myc/Max/USF binding site in the human p53 promoter reduces the transcription rate fivefold. The AP-1 motif in the human p53 promoter binds c-Fos and c-Jun and the NF-kappaB motif binds p50(NF-kappaB) and p65RelA. The cooperative nature of transcriptional activation by these factors was documented by repression of c-fos or NF-kappaB1 translation: Pretreatment of the cells with a c-fos or p50(NF-kappaB1) antisense oligonucleotide suppresses transcription from the human p53 promoter completely. In addition, we show that (a) the level of endogenous p53 mRNA and (b) transcription from the strictly p53-dependent human mdm2 promoter are reduced in the presence of c-fos, c-jun, p50(NF-kappaB1), p65RelA or c-myc antisense oligonucleotides, underscoring the importance of these transcription factors for the expression of functional p53.
Kirch
H C
HC
Institute of Molecular Biology (Cancer Research), University of Essen, Medical School, Germany.
Flaswinkel
S
S
Rumpf
H
H
Brockmann
D
D
Esche
H
H
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016158:Genes, p53; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D016376:Oligonucleotides, Antisense; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D018808:Transcription Factor AP-1; D014157:Transcription Factors