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The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription

Oncogene volume 22, pages 699–709 (2003)Cite this article

Abstract

The t(12;22) creates an MN1–TEL fusion gene leading to acute myeloid leukemia. The fusion partner TEL (ETV6) is a member of the ETS family of transcription factors. The nature of the other fusion partner, MN1, has not been investigated in detail until now. We recently described that MN1 activates the transcription activity of the moloney sarcoma virus long terminal repeat, indicating that this protein itself may act as a transcription factor. We show here that MN1 comprises multiple transcription activating domains. A search for a bound DNA sequence revealed that MN1 has affinity for retinoic acid responsive elements. A DR5 retinoic acid responsive element was observed in the LTR. The combination of MN1 and ligand-activated retinoic acid receptor leads to a synergistic induction of expression directed by the LTR. Cotransfection of MN1 with RAC3 or p300, known coactivators of retinoic acid receptors, leads to a further synergistic induction of transcription. In addition, the effect of MN1 can be inhibited by the wild-type adenovirus ElA protein that inhibits p300 function, but not by an E1A mutant lacking the p300-binding site. GAL4-MN1-mediated transcription can be enhanced directly by RAC3 and p300. Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.

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Acknowledgements

We thank Nicole Groen and Lydia van den Andel-Thijssen for their excellent technical assistance. We thank Drs D Chen, R Eckner, R Evans and JC Dorsman for permission to use RAC3, p300 and E1A expression constructs. This work was supported by Dutch Cancer Society grants EUR 94-653 and 98-1778, and in part by NCI Grant CA72996-04 and the American Lebanese Syrian Associated Charities (ALSAC) of St Jude Children's Hospital.

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  1. Karel H M van Wely and Anco C Molijn: The first two authors contributed equally to this paper

Authors and Affiliations

  1. Department of Pathology, Erasmus University, PO Box 1738, Rotterdam, 3000 DR, The Netherlands

    Karel H M van Wely, Anco C Molijn, Magda A Meester-Smoor, Albert Jan Aarnoudse, Anita Hellemons, Pim den Besten & Ellen C Zwarthoff

  2. Department of Hematology, University Hospital Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

    Arjan Buijs

  3. Department of Genetics, St. Jude's Children's Research Hospital, Memphis, 38101-0318, TN, USA

    Gerard C Grosveld

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  1. Karel H M van Wely
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Correspondence to Ellen C Zwarthoff.

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van Wely, K., Molijn, A., Buijs, A. et al. The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription. Oncogene 22, 699–709 (2003). https://doi.org/10.1038/sj.onc.1206124

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