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J. Biol. Chem., Vol. 282, Issue 4, 2211-2220, January 26, 2007

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FOXO3a Induces Differentiation of Bcr-Abl-transformed Cells through Transcriptional Down-regulation of Id1^*

Kim U. Birkenkamp¹², Abdelkader Essafi¹³, Kristan E. van der Vos⁴, Marco da Costa⁵, Rosaline C.-Y. Hui, Frank Holstege^¶, Leo Koenderman^||, Eric W.-F. Lam⁶⁷, and Paul J. Coffer⁶⁸

From the Molecular Immunology Laboratory, Department of Immunology, ^¶Department of Medical Genetics, and ^||Department of Pulmonary Diseases, University Medical Center, KC.02.085.2, Lundiaan 6, 3584-CX Utrecht, The Netherlands and the Cancer Research-UK Laboratories and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom

Leukemic transformation often requires activation of protein kinase B (PKB/c-Akt) and is characterized by increased proliferation, decreased apoptosis, and a differentiation block. PKB phosphorylates and inactivates members of the FOXO subfamily of Forkhead transcription factors. It has been suggested that hyperactivation of PKB maintains the leukemic phenotype through actively repressing FOXO-mediated regulation of specific genes. We have found expression of the transcriptional repressor Id1 (inhibitor of DNA binding 1) to be abrogated by FOXO3a activation. Inhibition of PKB activation or growth factor deprivation also resulted in strong down-regulation of Id1 promoter activity, Id1 mRNA, and protein expression. Id1 is highly expressed in Bcr-Abl-transformed K562 cells, correlating with high PKB activation and FOXO3a phosphorylation. Inhibition of Bcr-Abl by the chemical inhibitor STI571 resulted in activation of FOXO3a and down-regulation of Id1 expression. By performing chromatin immunoprecipitation assays and promoter-mutation analysis, we demonstrate that FOXO3a acts as a transcriptional repressor by directly binding to the Id1 promoter. STI571 treatment, or expression of constitutively active FOXO3a, resulted in erythroid differentiation of K562 cells, which was inhibited by ectopic expression of Id1. Taken together our data strongly suggest that high expression of Id1, through PKB-mediated inhibition of FOXO3a, is critical for maintenance of the leukemic phenotype.

Received for publication, July 13, 2006 , and in revised form, October 26, 2006.

^* This work was supported in part by the Dutch Scientific Organization (Grant NWO-90128139). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by the VENI Innovational Research Grant NWO-916.56.017.

³ Recipient of a grant from the Algerian Government.

⁴ Supported by the VIDI Innovational Research Grant NWO-917.36.316.

⁵ Supported by the Association for International Cancer Research (AICR).

⁶ These two authors are to be considered senior co-authors.

⁷ Supported by Leukemia Research Fund, AICR, and Cancer Research-UK.

⁸ To whom correspondence should be addressed. Tel.: 31-30-250-7134; Fax: 31-30-250-4305; E-mail: P.J.Coffer{at}umcutrecht.nl.

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