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PMID: 10490596 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein.

Molecular and cellular biology ·Vol. 19 ·No. 10 ·1999-10-00 ·Pages 6566-74

Fenrick R, Amann JM, Lutterbach B, Wang L, Westendorf JJ, Downing JR, Hiebert SW

Abstract

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.

MeSH Terms
Burkitt Lymphoma/genetics Child Chromosomes, Human, Pair 12 Chromosomes, Human, Pair 21 Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins/genetics,metabolism Humans Models, Genetic Neoplasm Proteins Oncogene Proteins, Fusion/genetics,metabolism Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins Proto-Oncogene Proteins c-ets RUNX1 Translocation Partner 1 Protein Repressor Proteins/genetics,metabolism Sin3 Histone Deacetylase and Corepressor Complex Transcription Factors/genetics,metabolism Translocation, Genetic
Chemicals
Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins ETS translocation variant 6 protein Neoplasm Proteins Oncogene Proteins, Fusion Proto-Oncogene Proteins Proto-Oncogene Proteins c-ets RUNX1 Translocation Partner 1 Protein RUNX1 protein, human RUNX1T1 protein, human Repressor Proteins SIN3A transcription factor TEL-AML1 fusion protein Transcription Factors Sin3 Histone Deacetylase and Corepressor Complex
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Fenrick R
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Amann J M
Lutterbach B
Wang L
Westendorf J J
Downing J R
Hiebert S W
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.19.10.6566
Published
1999-10-00
Pages
6566-74
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC84626
Subset
IM
Grants
NCI NIH HHS · R01 CA077274 · United States
NCI NIH HHS · P01 CA071907 · United States
NCI NIH HHS · P01 CA71907-03 · United States
NCI NIH HHS · R01-CA77274 · United States
NCI NIH HHS · P30 CA068485 · United States
NCI NIH HHS · F32 CA077167 · United States
NCI NIH HHS · R01-CA64140 · United States
NCI NIH HHS · R01 CA064140 · United States
External Links
PubMed source DOI: 10.1128/MCB.19.10.6566 PMC Full Text View journal details
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