Loss of p53 induces epidermal growth factor receptor promoter activity in normal human keratinocytes.
Overexpression of the epidermal growth factor receptor (EGFR) in human papillomavirus type 16-immortalized human keratinocytes (HKc) is caused by the viral oncoprotein E6, which targets p53 for degradation. We have previously observed that expression of p53 RNAi in normal HKc is associated with an increase in EGFR mRNA and protein. We now report that p53 RNAi induces EGFR promoter activity up to approximately 10-fold in normal HKc, and this effect does not require intact p53 binding sites on the EGFR promoter. Exogenous wild-type p53 inhibits the EGFR promoter at low levels, and activates it at higher concentrations. Yin Yang 1 (YY1), which negatively regulates p53, induces EGFR promoter activity, and this effect is augmented by p53 RNAi. Intact p53 binding sites on the EGFR promoter are not required for activation by YY1. In addition, Sp1 and YY1 synergistically induce the EGFR promoter in normal HKc, indicating that Sp1 may recruit YY1 as a co-activator. Wild-type p53 suppressed Sp1- and YY1-mediated induction of the EGFR promoter. We conclude that acute loss of p53 in normal HKc induces EGFR expression by a mechanism that involves YY1 and Sp1 and does not require p53 binding to the EGFR promoter.
Bheda
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Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, The South Carolina Cancer Center, Columbia, SC 29203, USA.
Creek
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Pirisi
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D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000502:physiology*; D005786:Gene Expression Regulation; D052162:Human papillomavirus 16 / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D016329:Sp1 Transcription Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D050986:YY1 Transcription Factor / Q000378:metabolism
D016329:Sp1 Transcription Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D066246:ErbB Receptors