Differential regulation of Foxo3a target genes in erythropoiesis.
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.
Bakker
Walbert J
WJ
Department of Hematology, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands.
van Dijk
Thamar B
TB
Parren-van Amelsvoort
Martine
M
Kolbus
Andrea
A
Yamamoto
Kazuo
K
Steinlein
Peter
P
Verhaak
Roel G W
RG
Mak
Tak W
TW
Beug
Hartmut
H
Löwenberg
Bob
B
von Lindern
Marieke
M
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D016000:Cluster Analysis; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D019089:Stem Cell Factor / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
C489552:Btg1 protein, mouse; C110087:Cited2 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor; D015534:Trans-Activators; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases