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Molecular and Cellular Biology, July 2000, p. 5019-5031, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

An Engineered PAX3-KRAB Transcriptional Repressor Inhibits the Malignant Phenotype of Alveolar Rhabdomyosarcoma Cells Harboring the Endogenous PAX3-FKHR Oncogene

William J. Fredericks, Kasirajan Ayyanathan, Meenhard Herlyn, Josh R. Friedman,dagger and Frank J. Rauscher III*

The Wistar Institute, Philadelphia, Pennsylvania 19104

Received 14 January 2000/Returned for modification 28 February 2000/Accepted 12 April 2000

The t(2;13) chromosomal translocation in alveolar rhabdomyosarcoma tumors (ARMS) creates an oncogenic transcriptional activator by fusion of PAX3 DNA binding motifs to a COOH-terminal activation domain derived from the FKHR gene. The dominant oncogenic potential of the PAX3-FKHR fusion protein is dependent on the FKHR activation domain. We have fused the KRAB repression module to the PAX3 DNA binding domain as a strategy to suppress the activity of the PAX3-FKHR oncogene. The PAX3-KRAB protein bound PAX3 target DNA sequences and repressed PAX3-dependent reporter plasmids. Stable expression of the PAX3-KRAB protein in ARMS cell lines resulted in loss of the ability of the cells to grow in low-serum or soft agar and to form tumors in SCID mice. Stable expression of a PAX3-KRAB mutant, which lacks repression function, or a KRAB protein alone, lacking a PAX3 DNA binding domain, failed to suppress the ARMS malignant phenotype. These data suggest that the PAX3-KRAB repressor functions as a DNA-binding-dependent suppressor of the transformed phenotype of ARMS cells, probably via competition with the endogenous PAX3-FKHR oncogene and repression of target genes required for ARMS tumorigenesis. The engineered repressor approach that directs a transcriptional repression domain to target genes deregulated by the PAX3-FKHR oncogene may be a useful strategy to identify the target genes critical for ARMS tumorigenesis.

* Corresponding author. Mailing address: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104. Phone: (215) 898-0995. Fax: (215) 898-3929. E-mail: rauscher{at}wistar.upenn.edu.

dagger Present address: The Children's Hospital of Pennsylvania, Philadelphia, PA 19104.

Molecular and Cellular Biology, July 2000, p. 5019-5031, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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