Abstract
The tumor suppressor protein p53 is a pivotal regulator of apoptosis, and prostate cancer cells that lack p53 protein are moderately resistant to apoptotic death by ionizing radiation. Genes encoding the transcription factor early growth response-1 (EGR-1) and cytokine tumor necrosis factor-alpha (TNF-alpha) were induced upon irradiation of prostate cancer cells, and inhibition of EGR-1 function resulted in abrogation of both TNF-alpha induction and apoptosis. Induction of the TNF-alpha gene by ionizing radiation and EGR-1 was mediated via a GC-rich EGR-1-binding motif in the TNF-alpha promoter. Because TNF-alpha induces apoptosis in prostate cancer cells, these findings suggest that, in the absence of p53, ionizing radiation-inducible apoptosis is mediated by EGR-1 via TNF-alpha transactivation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / radiation effects*
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Binding Sites
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Early Growth Response Protein 1
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Humans
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Immediate-Early Proteins*
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In Situ Hybridization, Fluorescence
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Mutagenesis, Site-Directed
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Radiation Tolerance / genetics
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcriptional Activation
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Transfection
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / genetics
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Tumor Suppressor Protein p53 / physiology*
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Up-Regulation
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Zinc Fingers*
Substances
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DNA-Binding Proteins
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EGR1 protein, human
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Early Growth Response Protein 1
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Immediate-Early Proteins
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53