Loss of p53 function through PAX-mediated transcriptional repression.
Direct interactions between the genes that regulate development and those which regulate the cell cycle would provide a mechanism by which numerous biological events could be better understood. We have identified a direct role for PAX5 in the control of p53 transcription. In primary human diffuse astrocytomas, PAX5 expression inversely correlated with p53 expression. The human p53 gene harbours a PAX binding site within its untranslated first exon that is conserved throughout evolution. PAX5 and its paralogues PAX2 and PAX8 are capable of inhibiting both the p53 promoter and transactivation of a p53-responsive reporter in cell culture. Mutation of the identified binding site eliminates PAX protein binding in vitro and renders the promoter inactive in cells. These data suggest that PAX proteins might regulate p53 expression during development and propose a novel alternative mechanism for tumour initiation or progression, by which loss of p53 function occurs at the transcriptional level.
Stuart
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Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Haffner
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Oren
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Gruss
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D016475:3T3 Cells; D000818:Animals; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051762:PAX2 Transcription Factor; D051757:PAX5 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C497282:Pax5 protein, mouse; C499496:Pax8 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53