Differential Regulation of Foxo3a Target Genes in Erythropoiesis<sup><a href="#fn3" rid="fn3" class=" fn">▿</a></sup> <sup><a href="#fn1" rid="fn1" class=" fn">†</a></sup>

Walbert Bakker

Thamar van Dijk

Martine Amelsvoort

Andrea Kolbus

Hartmut Beug+2 authors

Department of Hematology, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands,^{Research Institute of Molecular Pathology, A-1030 Vienna, Austria,}^{The Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada,}^{Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria}⁴

^{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:}ln.cmsumsare@nrednilnov.m

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

Received 2006 Sep 6; Revised 2006 Oct 8; Accepted 2007 Feb 20.

Abstract

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.

Abstract

Forkhead transcription factors regulate a multitude of developmental processes (40, 45). Subclass O (Foxo) of Forkhead transcription factors can be phosphorylated by protein kinase B (PKB), which results in transcriptional inactivation through nuclear export and cytosolic retention by 14-3-3 proteins (8, 13, 14, 39, 43, 68). Initial studies on the function of Foxo proteins in hematopoiesis pointed to a role in apoptosis and cell cycle regulation (9, 14, 17, 24). On the other hand, Foxo1 induces survival and maturation in thymocytes (46), and the activation of Foxo3a in erythroblasts induces differentiation, indicating that the role of Foxo proteins in hematopoiesis is diverse and probably cell type specific (4).

Erythroblasts can be expanded in vitro using serum-free medium supplemented with erythropoietin (Epo), stem cell factor (SCF), and glucocorticoids, which reflects the in vivo expansion of erythroblasts under stress conditions (7, 12, 25, 70). Immortal cultures of erythroblasts can reproducibly be established from p53^{mice (}60, 70). These cultures remain dependent on Epo, SCF, and glucocorticoids for their expansion and retain the ability to undergo complete differentiation into erythrocytes in the presence of Epo. The expansion of these cultures is dependent on Epo-induced activation of the tyrosine kinase receptor Ron/Stk (60), whereas differentiation relies on Epo-induced Stat5 phosphorylation (26). Both Epo and SCF activate the phosphatidylinositol 3-kinase (PI3K)-PKB pathway, although SCF induces phosphorylation of PKB more strongly (70). The inhibition of PI3K abrogates Epo/SCF-induced expansion of in vitro cultures, inducing differentiation instead, suggesting that pathways downstream of PI3K-PKB control the proliferation of erythroblasts (70). This was corroborated by in vivo experiments. Mice lacking the PI3K subunit p85 displayed transient fetal anemia with reduced numbers of burst-forming units-erythroid and CFU-erythroid (37). The lack of p85 did not increase apoptosis of erythroblasts and mast cells but decreased proliferation (29, 37, 48). Foxo3a^{^/}^{mice displayed compensated anemia with reticulocytosis, suggesting normal expansion but defects in erythrocyte maturation (}18).

Both SCF and Epo were able to inhibit the expression of Foxo3a target genes Cdkn1b (p27^{) and}Btg1. Nevertheless, SCF delays erythroid differentiation, while Epo enables erythroid differentiation. By consequence, Foxo3a targets may be differentially regulated by Epo and SCF. Two lines of evidence support this. First, Foxo proteins integrate a variety of signaling pathways, and examples show cooperation with transforming growth factor β signaling, IκB kinase, Wnt signaling, and the Jak-Stat pathway (27, 36, 44, 61). Furthermore, Foxo transcription factors can mediate gene expression independent of their DNA binding ability, underlining the importance of transcriptional coregulators (57, 68). Second, although Epo and SCF have overlapping functions (i.e., activation of the PI3K and Ras-mitogen-activated protein kinase pathways), there are also differences. Epo specifically activates the Jak-Stat pathway and the tyrosine kinase receptor Ron, which recruits the adaptor Gab1 (21, 67). Other targets are induced by both Epo and SCF but may have stimulus-specific effects. Epo and SCF activate Btk, but only SCF-induced Btk protects from Trail-induced apoptosis (60). Along similar lines, Epo and SCF may induce the differential regulation of Foxo3a target genes.

Finally, it is not known to what extent Foxo3a is involved in Epo/SCF-mediated repression of gene expression following factor deprivation (42), nor do we know to what extent all Foxo3a target genes are regulated by Epo/SCF-induced activation of the PI3K-PKB pathway. To analyze the relation between Epo- and SCF-controlled signal transduction and Foxo3a activity, we investigated Foxo3a-, Epo-, and SCF-induced gene expression on an expressed-sequence-tag (EST) microarray containing 17,000 cDNAs (17K EST cDNA array). We found that Foxo3a target genes are differentially affected by growth factor stimulation, and we analyzed two clusters of Foxo3a-upregulated genes in more detail. One cluster encompasses target genes that are repressed by Epo/SCF and upregulated in differentiation (Cdkn1b/p27^,Btg1, Ccng2/Cyclin G2, and Ulk1), while the other cluster contains genes that are less obviously inhibited by Epo/SCF and that are not upregulated during differentiation (Dcn, Sesn1, and Cited2). Interestingly, Cited2 appeared to be a Foxo3a target gene that was induced instead of repressed by Epo. Data presented demonstrate that the alleged growth-stimulatory transcription factor Stat5 cooperates with the alleged growth-inhibitory transcription factor Foxo3a to control the expression of Cited2. In contrast, the upregulation of Btg1 during differentiation appeared to be reinforced by the cooperation of Foxo3a with the cyclic AMP (cAMP)-responsive transcription factor CREB/ATF1. Our data imply that Foxo3a functions to integrate and transmit multiple signals that cooperate to regulate the gene expression program of erythroblasts.

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Acknowledgments

We thank H. van Dam (LUMC, Leiden, The Netherlands) and I. P. Touw for many critical discussions regarding the work presented, Kim Birkenkamp (UMC, Utrecht, The Netherlands) for detailed information on Ba/F3 cell electroporation, Herbert Auer (IMP, Vienna, Austria) for his patient help with the array analysis, Mark Kerenyi (IMP, Vienna, Austria) for Stat5^{fetal livers, and Victor de Jager (Erasmus MC) for his help in bioinformatics.}

This work was supported by grants from the Dutch Cancer Society (EUR 2000-2230), The Netherlands Organization for Scientific Research (050-10-051), the European Union (HPRN-CT-2000-00083), an Erasmus fellowship to T.B.V.D., and a fellowship of the Dutch Academy of Arts and Sciences to M.V.L.

Acknowledgments

Footnotes

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

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

Footnotes

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