p53 Homologue p63 represses epidermal growth factor receptor expression.
Tumor suppressor p53 has been shown to transactivate epidermal growth factor receptor (EGFR) expression through binding to a putative p53 responsive element in the EGFR promoter between nucleotides -265 and -239 (EGFRp53RE). Isotypes of p63 gene products, recently identified as p53 relatives, have a similar function to transactivate several p53 target gene promoters. However, our results indicate that TAp63gamma has a very low ability to bind to the EGFRp53RE and surprisingly represses both basal EGFR promoter activity and endogenous EGFR expression. Transient transfection assays show that the EGFR promoter region between -348 and -293, containing two Sp1 sites, is crucial for the repression of the EGFR expression by TAp63gamma. Mutations in these Sp1 sites in the reporter constructs result in loss of the TAp63gamma repression effect. We further show that TAp63gamma directly interacts with Sp1 by immunoprecipitation analysis and that TAp63gamma impairs Sp1 binding to the target DNA site in electrophoretic mobility shift assays. These results suggest that TAp63gamma is involved in the regulation of the EGFR gene expression through interactions with basal transcription factors.
Nishi
H
H
Laboratory of Molecular Biology, CCR, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
Senoo
M
M
Nishi
K H
KH
Murphy
B
B
Rikiyama
T
T
Matsumura
Y
Y
Habu
S
S
Johnson
A C
AC
D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D066246:ErbB Receptors / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000502:physiology*; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D004247:DNA; D066246:ErbB Receptors