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Delta Np73 Enhances Promoter Activity of TGF-beta Induced Genes

Niemantsverdriet, M., Nagle, P., Chiu, R. K., Langendijk, J. A., Kampinga, H. H. & Coppes, R. P., 7-Dec-2012, In : PLoS ONE. 7, 12, 10 p., e50815.

Research output: Contribution to journalArticleAcademicpeer-review

The p53 homolog p73 is frequently overexpressed in cancers. Especially the transactivation domain truncated isoform Delta Np73 has oncogenic properties and its upregulation is associated with poor patient survival. It has been shown that Delta Np73 has an inhibitory effect on the transactivation capacity of p53 and other p73 isoforms. Here, we confirm this finding but surprisingly find that Delta Np73 may also stimulate the expression of TGF-beta 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 Delta Np73. TGF-beta signaling was less efficient in Delta Np73 downregulated cells, whereas tetracycline induced Delta Np73 increased expression of endogenous TGF-beta regulated genes PAI-1 and Col1a1. Pull-down assays with SBE DNA suggest that Delta Np73 enhances smad3/4 binding to SBEs, thereby stimulating TGF-beta signaling. Chromatin immunoprecipitation assays confirmed a direct interaction between Delta Np73 and SBE. Given the role of TGF-beta signaling in carcinogenesis, tumor invasion and metastasis via targets like PAI-1 and Col1a1, our data suggest a model on how this effect of Delta Np73 could be a contributing factor in cancer progression.

Original languageEnglish
Article numbere50815
Number of pages10
JournalPLoS ONE
Volume7
Issue number12
Publication statusPublished - 7-Dec-2012

    Keywords

  • GROWTH-FACTOR-BETA, SQUAMOUS-CELL CARCINOMA, SPONTANEOUS TUMORS, SERIAL ANALYSIS, MICE DEFICIENT, P53, CANCER, EXPRESSION, P73, IDENTIFICATION

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