Abstract
Adult T-cell leukemia (ATL) is a mature CD4+ T-cell malignancy etiologically associated with human T-cell leukemia virus type 1 (HTLV-1). Primary ATL cells frequently express CCR4 at high levels. Since HTLV-1 Tax does not induce CCR4 expression, transcription factor(s) constitutively active in ATL may be responsible for its strong expression. We identified an activator protein-1 (AP-1) site in the CCR4 promoter as the major positive regulatory element in ATL cells. Among the AP-1 family members, Fra-2, JunB and JunD are highly expressed in fresh primary ATL cells. Consistently, the Fra-2/JunB and Fra-2/JunD heterodimers strongly activated the CCR4 promoter in Jurkat cells. Furthermore, Fra-2 small interfering RNA (siRNA) or JunD siRNA, but not JunB siRNA, effectively reduced CCR4 expression and cell growth in ATL cells. Conversely, Fra-2 or JunD overexpression promoted cell growth in Jurkat cells. We identified 49 genes, including c-Myb, BCL-6 and MDM2, which were downregulated by Fra-2 siRNA in ATL cells. c-Myb, BCL-6 and MDM2 were also downregulated by JunD siRNA. As Fra-2, these proto-oncogenes were highly expressed in primary ATL cells but not in normal CD4+ T cells. Collectively, aberrantly expressed Fra-2 in association with JunD may play a major role in CCR4 expression and oncogenesis in ATL.
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Acknowledgements
We thank Namie Sakiyama for her excellent technical assistance. We also thank Dr Rich Simon and Dr Amy Peng for providing the BRB ArrayTools software. This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports and Technology, Japan; by Solution-Oriented Research for Science and Technology (SORST) from Japan Science and Technology Corporation and by High-Tech Research Center Project for Private Universities: matching fund subsidy from the Ministry of Education, Culture, Sports, Science and Technology of Japan, 2002–2009.
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Nakayama, T., Hieshima, K., Arao, T. et al. Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia. Oncogene 27, 3221–3232 (2008). https://doi.org/10.1038/sj.onc.1210984
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DOI: https://doi.org/10.1038/sj.onc.1210984
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