The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling.
The PTEN tumour suppressor and pro-apoptotic gene is frequently mutated in human cancers. We show that PTEN transcription is upregulated by Egr-1 after irradiation in wild-type, but not egr-1-/-, mice in vivo. We found that Egr-1 specifically binds to the PTEN 5' untranslated region, which contains a functional GCGGCGGCG Egr-1-binding site. Inducing Egr-1 by exposing cells to ultraviolet light upregulates expression of PTEN messenger RNA and protein, and leads to apoptosis. egr-1-/- cells, which cannot upregulate PTEN expression after irradiation, are resistant to ultraviolet-light-induced apoptosis. Therefore, Egr-1 can directly regulate PTEN, triggering the initial step in this apoptotic pathway. Loss of Egr-1 expression, which often occurs in human cancers, could deregulate the PTEN gene and contribute to the radiation resistance of some cancer cells.
Virolle
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The Burnham Institute, Cancer Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Adamson
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Baron
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Birle
D
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Mercola
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D
Mustelin
T
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de Belle
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I
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D020405:Dermis / Q000166:cytology; D051766:Early Growth Response Protein 1; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D017874:Immediate-Early Proteins; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000503:physiopathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D005047:Etoposide; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human