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Numata, A, Shimoda, K, Kamezaki, K, Haro, T, Kakumitsu, H, Shide, K, Kato, K, Miyamoto, T, Yamashita, Y, Oshima, Y, Nakajima, H, Iwama, A, Aoki, K, Takase, K, Gondo, H, Mano, H and Harada, M (2005) Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer-binding protein alpha in granulocyte colony-stimulating factor signaling pathway. J. Biol. Chem. 280:12621-9
The Janus kinase (Jak)-Stat pathway plays an essential role in cytokine signaling. Granulocyte colony-stimulating factor (G-CSF) promotes granulopoiesis and granulocytic differentiation, and Stat3 is the principle Stat protein activated by G-CSF. Upon treatment with G-CSF, the interleukin-3-dependent cell line 32D clone 3(32Dcl3) differentiates into neutrophils, and 32Dcl3 cells expressing dominant-negative Stat3 (32Dcl3/DNStat3) proliferate in G-CSF without differentiation. Gene expression profile and quantitative PCR analysis of G-CSF-stimulated cell lines revealed that the expression of C/EBPalpha was up-regulated by the activation of Stat3. In addition, activated Stat3 bound to CCAAT/enhancer-binding protein (C/EBP)alpha, leading to the enhancement of the transcription activity of C/EBPalpha. Conditional expression of C/EBPalpha in 32Dcl3/DNStat3 cells after G-CSF stimulation abolishes the G-CSF-dependent cell proliferation and induces granulocytic differentiation. Although granulocyte-specific genes, such as the G-CSF receptor, lysozyme M, and neutrophil gelatinase-associated lipocalin precursor (NGAL) are regulated by Stat3, only NGAL was induced by the restoration of C/EBPalpha after stimulation with G-CSF in 32Dcl3/DNStat3 cells. These results show that one of the major roles of Stat3 in the G-CSF signaling pathway is to augment the function of C/EBPalpha, which is essential for myeloid differentiation. Additionally, cooperation of C/EBPalpha with other Stat3-activated proteins are required for the induction of some G-CSF responsive genes including lysozyme M and the G-CSF receptor.
Acute-Phase Proteins/metabolism; Animals; Blotting, Western; CCAAT-Enhancer-Binding Protein-alpha/metabolism; Cell Differentiation; Cell Line; Cell Proliferation; Cytokines/metabolism; DNA-Binding Proteins/metabolism; DNA-Binding Proteins/physiology; Flow Cytometry; Gene Expression Regulation; Genes, Dominant; Granulocyte Colony-Stimulating Factor/metabolism; Granulocytes/cytology; Granulocytes/metabolism; Humans; Immunoblotting; Immunoprecipitation; Interferon-alpha/metabolism; Interleukin-3/metabolism; Lipocalins; Mice; Muramidase/chemistry; Muramidase/metabolism; Myeloid Cells/metabolism; Neutrophils/metabolism; Oligonucleotide Array Sequence Analysis; Oncogene Proteins/metabolism; Promoter Regions, Genetic; Proto-Oncogene Proteins; RNA, Messenger/metabolism; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Signal Transduction; Time Factors; Trans-Activators/metabolism; Trans-Activators/physiology; Transcription, Genetic
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