Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia.
Transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is essential for granulopoiesis and its function is deregulated in leukemia. Inhibition of E2F1, the master regulator of cell-cycle progression, by C/EBPalpha is pivotal for granulopoiesis. Recent studies show microRNA-223 (miR-223), a transcriptional target of C/EBPalpha, as a critical player during granulopoiesis. In this report, we demonstrate that during granulopoiesis microRNA-223 targets E2F1. E2F1 protein was up-regulated in miR-223 null mice. We show that miR-223 blocks cell-cycle progression in myeloid cells. miR-223 is down-regulated in different subtypes of acute myeloid leukemia (AML). We further show that E2F1 binds to the miR-223 promoter in AML blast cells and inhibits miR-223 transcription, suggesting that E2F1 is a transcriptional repressor of the miR-223 gene in AML. Our study supports a molecular network involving miR-223, C/EBPalpha, and E2F1 as major components of the granulocyte differentiation program, which is deregulated in AML.
Pulikkan
John A
JA
Department of Internal Medicine IV-Oncology and Hematology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Dengler
Viola
V
Peramangalam
Philomina S
PS
Peer Zada
Abdul A
AA
Müller-Tidow
Carsten
C
Bohlander
Stefan K
SK
Tenen
Daniel G
DG
Behre
Gerhard
G
D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D025461:Feedback, Physiological; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019891:Leukopoiesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D015854:Up-Regulation
D022763:CCAAT-Enhancer-Binding Protein-alpha; D017931:DNA Primers; D050687:E2F1 Transcription Factor; D035683:MicroRNAs; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; C525067:MIR223, human; C544877:MIRN223 microRNA, mouse