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Acetylation of FOXO3a transcription factor in response to imatinib of chronic myeloid leukemia

Leukemia volume 23, pages 405–406 (2009)Cite this article

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Members of the FOXO subfamily of forkhead transcription factors, including FOXO1 (FKHR), FOXO3a (FKHRL1), FOXO4 (AFX) and FOXO6 in humans, are key regulators of cell cycle progression, DNA damage repair, reactive oxygen species detoxification, apoptosis and autophagy. Post-translational modifications (phosphorylation, acetylation and ubiquitination) regulate the transcriptional activity of FOXO proteins by directing their subcellular location, DNA binding and stability.1 Phosphorylation by the phosphatidyl-inositol 3-OH kinase/AKT axis at three highly conserved AKT recognition sites within N- and C-terminal regions is the most extensively studied post-translational modification of FOXO proteins. Two phosphorylation sites (Thr24 and Ser256 in FOXO1 corresponding to Thr32 and Ser253 in FOXO3a) create binding motifs for the 14-3-3 scaffolding proteins thereby causing the translocation of FOXO and its retention in the cytoplasm.1 Moreover, 14-3-3 binding to phosphorylated Ser253 in FOXO3a masks a cluster of three adjacent basic residues (Arg248, Arg249 and Arg250), thereby weakening its DNA-binding affinity.2 The third phosphorylation site (Ser319 in FOXO1 corresponding to Ser315 in FOXO3a) creates a consensus sequence for casein kinase 1 promoting further phosphorylations at serine residues that potentiate the nuclear export of FOXO through interactions with the export machinery.1 More recently, acetylation has been involved in the subcellular location and transcriptional regulation of FOXO. It is induced in response to oxidative stress by enhanced interactions with histone acetyltransferases p300/c-AMP-response element-binding protein-binding protein (CBP) and p300/CBP-associated factor and promotes the nuclear import of FOXO.3 Following acetylation, FOXO activities are integrated by the recruitment of sirtuin 1, a nicotinamide adenine dinucleotide-dependent deacetylase.1, 3 The precise roles of acetyltransferases and deacetylases in the transcriptional regulation of FOXO are not known. Recent studies proved that FOXO3a acetylation at three Lys residues (Lys242, Lys245 and Lys259) in the C-terminus of its DNA-binding domain promotes the disruption of protein–DNA contacts and increases the accessibility to AKT phosphorylation at Ser253 thereby attenuating its transcriptional activity.2, 4

FOXO3a is involved in the pathogenesis of chronic myeloid leukemia. Its constitutive phosphorylation by p210BCR-ABL tyrosine kinase (TK) through the phosphatidyl-inositol 3-OH kinase/AKT pathway contributes to the proliferative and survival advantage of leukemic progenitors. Accordingly, p210BCR-ABL inhibition by imatinib mesylate (IM, also referred to as STI571 or Glevec) restores FOXO3a functions on cell cycle progression and apoptosis of chronic myeloid leukemic cells through the induction of cyclin-dependent kinase inhibitor p27Kip1 and pro-apoptotic BCL-2L11 BCL-2LIKE 11 (BIM).5, 6 Here we investigated the impact of p210BCR-ABL on the acetylation status of FOXO3a. For this purpose, we used a cell clone (3B) generated from 32D murine myeloid progenitor cell line expressing a temperature-sensitive BCR-ABL construct, whose protein possesses TK activity at the permissive temperature of 33 °C, but not at the non-permissive temperature of 39 °C.

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Acknowledgements

This study was supported by University of Bologna, BolognaAIL and Carisbo Foundation. PC and MM are recipients of grants provided by the Istituto di Radioterapia ‘Luigi Galvani’, University of Bologna-Medical School.

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  1. Dipartimento di Ematologia e Scienze Oncologiche ‘Lorenzo e Ariosto Seràgnoli’, University of Bologna-Medical School, Bologna, Italy

    P Corrado, M Mancini, G Brusa, S Petta, G Martinelli & M A Santucci

  2. Dipartimento di Scienze Radiologiche ed Istopatologiche L Galvani, University of Bologna-Medical School, Bologna, Italy

    E Barbieri

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  1. P Corrado
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Correspondence to M Mancini.

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Corrado, P., Mancini, M., Brusa, G. et al. Acetylation of FOXO3a transcription factor in response to imatinib of chronic myeloid leukemia. Leukemia 23, 405–406 (2009). https://doi.org/10.1038/leu.2008.186

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