title: ΔNp73 enhances promoter activity of TGF-β induced genes.
abstract: The p53 homolog p73 is frequently overexpressed in cancers. Especially the transactivation domain truncated isoform ΔNp73 has oncogenic properties and its upregulation is associated with poor patient survival. It has been shown that ΔNp73 has an inhibitory effect on the transactivation capacity of p53 and other p73 isoforms. Here, we confirm this finding but surprisingly find that ΔNp73 may also stimulate the expression of TGF-β signaling targets. Promoter-reporter analysis indicated that the presence of Smad Binding Elements (SBE) in the promoter is sufficient for stimulation of gene expression by ΔNp73. TGF-β signaling was less efficient in ΔNp73 downregulated cells, whereas tetracycline induced ΔNp73 increased expression of endogenous TGF-β regulated genes PAI-1 and Col1a1. Pull-down assays with SBE DNA suggest that ΔNp73 enhances smad3/4 binding to SBEs, thereby stimulating TGF-β signaling. Chromatin immunoprecipitation assays confirmed a direct interaction between ΔNp73 and SBE. Given the role of TGF-β signaling in carcinogenesis, tumor invasion and metastasis via targets like PAI-1 and Col1a1, our data suggest a model on how this effect of ΔNp73 could be a contributing factor in cancer progression.
authors.affiliation: Department of Cell Biology, Section Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Niemantsverdriet
authors.forename: Peter
authors.initials: P
authors.lastname: Nagle
authors.forename: Roland K
authors.initials: RK
authors.lastname: Chiu
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.forename: Robert P
authors.initials: RP
authors.lastname: Coppes
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D017395:Plasminogen Activator Inhibitor 1; D051900:Smad3 Protein; C000606460:TP73 protein, human; D016212:Transforming Growth Factor beta; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human