Phosphorylation regulates transcriptional activity of PAX3/FKHR and reveals novel therapeutic possibilities

Inhibition of constitutive active signaling pathways, which are a characteristic phenomenon for many tumors, can be an effective therapeutic strategy. In contrast, oncogenic transcription factors, often activated by mutational events, are in general less amenable to small-molecule inhibition despite...

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Published inCancer research (Chicago, Ill.) Vol. 68; no. 10; pp. 3767 - 3776
Main Authors Amstutz, Ralf, Wachtel, Marco, Troxler, Heinz, Kleinert, Peter, Ebauer, Margret, Haneke, Torsten, Oehler-Jänne, Christoph, Fabbro, Doriano, Niggli, Felix K, Schäfer, Beat W
Format Journal Article
LanguageEnglish
Published United States 15.05.2008
Subjects
Animals
Antineoplastic Agents - pharmacology
Forkhead Box Protein O1
Forkhead Transcription Factors - metabolism
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Paired Box Transcription Factors - metabolism
PAX3 Transcription Factor
Phosphorylation
Rhabdomyosarcoma - drug therapy
RNA Processing, Post-Transcriptional
Staurosporine - analogs & derivatives
Staurosporine - pharmacology
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Summary:Inhibition of constitutive active signaling pathways, which are a characteristic phenomenon for many tumors, can be an effective therapeutic strategy. In contrast, oncogenic transcription factors, often activated by mutational events, are in general less amenable to small-molecule inhibition despite their obvious importance as therapeutic targets. One example of this is alveolar rhabdomyosarcoma (aRMS), in which specific translocations lead to the formation of the chimeric transcription factor PAX3/FKHR. Here, we found unexpectedly that the transcriptional activity of PAX3/FKHR can be inhibited by the kinase inhibitor PKC412. This occurs via specific phosphorylation sites in the PAX3 domain, phosphorylation of which is required for efficient DNA-binding and subsequent transcriptional activity. Consequently, we show that PKC412 exerts a potent antitumorigenic potential for aRMS treatment both in vitro and in vivo. Our study suggests that posttranscriptional modifications of oncogenic transcription factors can be explored as a promising avenue for targeted cancer therapy.
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ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-07-2447