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Molecular and Cellular Biology, October 1999, p. 6566-6574, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Both TEL and AML-1 Contribute Repression Domains to the t(12;21) Fusion Protein

Randy Fenrick,1,2 Joseph M. Amann,1,2 Bart Lutterbach,1,2 Lilin Wang,1,2 Jennifer J. Westendorf,1,2 James R. Downing,3 and Scott W. Hiebert1,2,*

Department of Biochemistry1 and Vanderbilt Cancer Center,2 Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and Department of Pathology and Laboratory of Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee 381053

Received 17 February 1999/Returned for modification 1 April 1999/Accepted 9 July 1999

t(12;21) is the most frequent translocation found in pediatric B-cell acute lymphoblastic leukemias. This translocation fuses a putative repressor domain from the TEL DNA-binding protein to nearly all of the AML-1B transcription factor. Here, we demonstrate that fusion of the TEL pointed domain to the GAL4 DNA-binding domain resulted in sequence-specific transcriptional repression, indicating that the pointed domain is a portable repression motif. The TEL pointed domain functioned equally well when the GAL4 DNA-binding sites were moved 600 bp from the promoter, suggesting an active mechanism of repression. This lead us to demonstrate that wild-type TEL and the t(12;21) fusion protein bind the mSin3A corepressor. In the fusion protein, both TEL and AML-1B contribute mSin3 interaction domains. Deletion mutagenesis indicated that both the TEL and AML-1B mSin3-binding domains contribute to repression by the fusion protein. While both TEL and AML-1B associate with mSin3A, TEL/AML-1B appears to bind this corepressor much more stably than either wild-type protein, suggesting a mode of action for the t(12;21) fusion protein.

* Corresponding author. Mailing address: Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Rm. 512 Medical Research Building II, 23rd and Pierce, Nashville, TN 37232. Phone: (615) 936-3582. Fax: (615) 936-1790. E-mail: scott.hiebert{at}mcmail.vanderbilt.edu.

Molecular and Cellular Biology, October 1999, p. 6566-6574, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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