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Molecular and Cellular Biology, May 2007, p. 3839-3854, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.01662-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Differential Regulation of Foxo3a Target Genes in Erythropoiesis{triangledown} ,{dagger}

Walbert J. Bakker,1,3 Thamar B. van Dijk,1,{ddagger} Martine Parren-van Amelsvoort,1 Andrea Kolbus,2,4 Kazuo Yamamoto,3 Peter Steinlein,2 Roel G. W. Verhaak,1 Tak W. Mak,3 Hartmut Beug,2 Bob Löwenberg,1 and Marieke von Lindern1*

Department of Hematology, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands,1 Research Institute of Molecular Pathology, A-1030 Vienna, Austria,2 The Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada,3 Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria4

Received 6 September 2006/ Returned for modification 8 October 2006/ Accepted 20 February 2007

The cooperation of stem cell factor (SCF) and erythropoietin (Epo) is required to induce renewal divisions in erythroid progenitors, whereas differentiation to mature erythrocytes requires the presence of Epo only. Epo and SCF activate common signaling pathways such as the activation of protein kinase B (PKB) and the subsequent phosphorylation and inactivation of Foxo3a. In contrast, only Epo activates Stat5. Both Foxo3a and Stat5 promote erythroid differentiation. To understand the interplay of SCF and Epo in maintaining the balance between renewal and differentiation during erythroid development, we investigated differential Foxo3a target regulation by Epo and SCF. Expression profiling revealed that a subset of Foxo3a targets was not inhibited but was activated by Epo. One of these genes was Cited2. Transcriptional control of Epo/Foxo3a-induced Cited2 was studied and compared with that of the Epo-repressed Foxo3a target Btg1. We show that in response to Epo, the allegedly growth-inhibitory factor Foxo3a associates with the allegedly growth-stimulatory factor Stat5 in the nucleus, which is required for Epo-induced Cited2 expression. In contrast, Btg1 expression is controlled by the cooperation of Foxo3a with cyclic AMP- and Jun kinase-dependent Creb family members. Thus, Foxo3a not only is an effector of PKB but also integrates distinct signals to regulate gene expression in erythropoiesis.

* Corresponding author. Mailing address: Department of Hematology, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31 10 408 7961. Fax: 31 10 408 9470. E-mail: m.vonlindern{at}erasmusmc.nl

{triangledown} Published ahead of print on 12 March 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Cell Biology and Genetics, Erasmus MC, Rotterdam, The Netherlands.

Molecular and Cellular Biology, May 2007, p. 3839-3854, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.01662-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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