期刊
BLOOD
卷 116, 期 14, 页码 2462-2471出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-12-259630
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资金
- NCI [P30CA16672]
- National Institutes of Health [AI073587]
- Center for Stem Cell and Developmental Biology at MDACC
- [T32-CA-09598-16]
Granulocyte colony-stimulating factor (G-CSF) mediates emergency granulopoiesis during infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the intracellular signaling cascades that control demand-driven neutrophil production. Using a murine model with conditional deletion of signal transducer and activator of transcription 3 (STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of STAT3 function in the emergency granulopoiesis response to G-CSF administration or infection with Listeria monocytogenes, a pathogen that is restrained by G-CSF signaling in vivo. Our results show that STAT3 deficiency renders hematopoietic progenitor cells and myeloid precursors refractory to the growth-promoting functions of G-CSF or L monocytogenes infection. STAT3 is necessary for accelerating granulocyte cell-cycle progression and maturation in response to G-CSF. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein beta (C/EBP beta), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBP beta coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBP alpha occupancy during demand-driven granulopoiesis. These results place STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. (Blood. 2010;116(14):2462-2471)
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