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p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

Oncogene volume 18, pages 4958–4967 (1999)Cite this article

Abstract

Activation of the TAL1 (or SCL) gene, originally identified through its involvement by a recurrent chromosomal translocation, is the most frequent gain-of-function mutation recognized in T-cell acute lymphoblastic leukemia (T-ALL). The TAL1 proteins contain a basic helix – loop – helix (bHLH) motif characteristic of a large family of transcription factors that control transcription from an E box target element as heterodimers with the E2A- and HEB-encoded gene products. Gene knockout studies in mice indicate that this transcription factor is required for embryonic and adult hematopoiesis, and considerable evidence suggests it has specific functions in terminal erythroid differentiation. We investigated whether the broadly expressed nuclear protein p300, known to function as a coactivator for other bHLH proteins involved in cellular differentiation, also interacts with TAL1. p300 was found to coimmunoprecipitate with Tal1 in extracts from murine erythroleukemia (MEL) cells induced to differentiate with dimethylsulfoxide (DMSO), and p300 and Tal1 were observed in a common E box DNA-binding complex in extracts from differentiating MEL cells. p300 also interacted with Tal1 in protein pulldown assays, suggesting this was a direct interaction. Finally, p300 augmented transcription by Tal1 from an E box-containing promoter and by a GAL4-Tal1 fusion from a promoter containing the GAL4 DNA-binding element. Deletion analysis identified the bHLH domain of Tal1 and amino-terminal sequences of p300 as necessary for p300-stimulated transactivation and Tal1-p300 interaction in vitro. These results indicate that recruitment of the transcriptional coactivator p300 can positively regulate TAL1-directed gene expression. The dependence of their interaction in MEL cells on addition of a differentiation inducer suggests, further, that this TAL1-p300 complex may have an important role in terminal erythroid differentiation.

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Abbreviations

T-ALL:

T-cell acute lymphoblastic leukemia

bHLH:

basic region helix – loop – helix

DMSO:

dimethylsulfoxide

CBP:

CREB-binding protein

CAT:

chloramphenicol acetyltransferase

PAGE:

polyacrylamide gel electrophoresis

EMSA:

electrophoretic mobility shift assay

DTT:

dithiothreitol

GST:

glutathione S-transferase

BSA:

bovine serum albumin

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Acknowledgements

We thank Richard Eckner and David Livingston for p300 cDNAs, Mark Ptashne for GAL4 constructs, Glenn Begley for the full-length Tal1 cDNA, Richard Baer for E box reporter plasmids, and Elizabeth Moran for antibodies. This work was supported in part by United States Public Health Service Grants R01 HL49118 (to SJ Brandt) and R01 DK55091 (to RW Stein) and an American Society of Hematology Fellow Scholar Award (to S Huang).

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, Tennessee, USA

    Suming Huang & Stephen J Brandt

  2. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, Tennessee, USA

    Yi Qiu & Roland W Stein

  3. Department of Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232, Tennessee, USA

    Roland W Stein & Stephen J Brandt

  4. Department of Veterans Affairs Medical Center, Nashville, TN 37232, Tennessee, USA

    Stephen J Brandt

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Huang, S., Qiu, Y., Stein, R. et al. p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein. Oncogene 18, 4958–4967 (1999). https://doi.org/10.1038/sj.onc.1202889

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