p73 transcriptional activity increases upon cooperation between its spliced forms.
The p53 homologue p73 efficiently activates p53-responsive genes. The well documented over-expression of p73 spliced forms in a wide variety of tumor types promoted us to elucidate the mechanisms underlying p73-mediated transcription. Using the luciferase reporter gene driven by Mdm2-minimal promoter in p53 null cells, we demonstrate that the weak transcriptional activity mediated by p73alpha was increased by the mutant form p73beta292, which by itself is transcriptionally inactive. Similarly, cooperation between p73beta and an inactive form of p73alpha increased p73beta-mediated transcriptional activities. Conversely, p73beta elicited a silencing effect on a gain of function mutant, p53(281), which by itself mediated efficient transactivation of the MDR promoter. Neither anisomycin nor actinomycin D altered p73-mediated transcriptional activities, whereas sorbitol profoundly inhibited them through a rapid proteasome-dependent degradation of p73. Our observations point to plausible scenarios in which p73, through cooperation between p73 spliced forms and suppression of gain of function mutant p53 may elicit changes in the transcription of p53 target genes that play key roles in cell growth and death.
Alarcon-Vargas
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Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029, USA.
Fuchs
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Deb
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Ronai
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D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005813:Genes, Synthetic; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D006982:Hypertonic Solutions / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D012326:RNA Splicing; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013012:Sorbitol / Q000494:pharmacology; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D006982:Hypertonic Solutions; D007976:Leupeptins; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003609:Dactinomycin; D013012:Sorbitol; D000841:Anisomycin; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde