Article

Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer-binding protein α in granulocyte colony-stimulating factor signaling pathway

Kyushu University, Hukuoka, Fukuoka, Japan
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2005; 280(13):12621-9. DOI: 10.1074/jbc.M408442200
Source: PubMed

ABSTRACT 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.

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    • "Using the TRANSFAC database, we identified a number of putative transcription factor binding sites in the -472/-345 region, including sites for C/EBP (-444/CAAC/-441) and GATA-1 (-435/TATCT/-431) (Figure 1b). Because these transcription factors are activated in some cases of tumorigenesis [24,25], we speculated that they contributed to the increased transcription of Jab1. "
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    • "For example, Stat3 has been shown to interact directly with NF-κB forming a complex that synergistically promotes target genes expression [50,51]. Stat3 could also cooperate with C/EBPs [47], CREB [52], or AP-1 [53,54] to regulate target gene expression by binding to either its consensus sites or the non-consensus regions [51,55]. Regardless of how Stat3 contributes to the regulation of IL-6 expression, Stat3 DNA-binding activity is required. "
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