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TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3

Oncogene volume 20, pages 3716–3725 (2001)Cite this article

Abstract

TEL (Translocation–ETS–Leukemia or ETV 6) is disrupted by multiple chromosomal translocations in acute leukemia. The loss of heterozygosity at the TEL locus in leukemias and the hemizygous deletion of TEL that is observed in various tumors, suggests that TEL is a tumor suppressor. Overexpression of TEL alters cellular morphology and represses the expression of the matrix metalloproteinase stromelysin-1. Based on these studies, deletion analysis was used to define the minimal repression domains of TEL. TEL-mediated repression required both the N-terminal pointed domain and a central region composed of amino acids 268–303. The mSin3A and N-CoR corepressors bind to the pointed domain and the central repression domain of TEL, respectively. Unexpectedly, histone deacetylase-3, but not other histone deacetylases, also associates with the central region of TEL. Histone deacetylase-3 interacts with a TEL mutant that cannot bind N-CoR, suggesting that this is a direct interaction with TEL. In addition, histone H3 was under-acetylated near the TEL-binding sites in the endogenous stromelysin-1 promoter when TEL was expressed. Furthermore, trichostatin A, a potent histone deacetylase inhibitor, impaired TEL-dependent repression of the stromelysin-1 promoter. Finally, while TEL-expression induced cellular aggregation of Ras-transformed cells, Trichostatin A reversed the TEL-induced cellular aggregation phenotype. Thus, the cumulative data suggests that histone deacetylase-3 activity is required for the transcriptional functions of TEL.

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Acknowledgements

We thank Yue Hou for technical assistance, and members of the Hiebert laboratory for helpful discussions and especially Drs Joseph Amann and Lauren Wood for critically reading the manuscript. The experiments described here were performed in part through the use of the VICC sequencing facility, which is supported by NIH grant CA68465. This work was also supported by NIH/NCI grant RO1-CA77274 (to SW Hiebert), and by the Vanderbilt-Ingram Cancer Center.

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  1. Department of Biochemistry and the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, TN, USA

    Lilin Wang & Scott W Hiebert

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Wang, L., Hiebert, S. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene 20, 3716–3725 (2001). https://doi.org/10.1038/sj.onc.1204479

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