期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 281, 期 16, 页码 10745-10751出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M510924200
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资金
- NCI NIH HHS [R01 CA092172, R01CA92172] Funding Source: Medline
Granulocyte-colony-stimulating factor (G-CSF) stimulates the activation of multiple signaling pathways, leading to alterations in the activities of transcription factors. Gfi-1 is a zinc finger transcriptional repressor that is required for granulopoiesis. How Gfi-1 acts in myeloid cells is poorly understood. We show here that the expression of Gfi-1 was up-regulated during G-CSF-induced granulocytic differentiation in myeloid 32D cells. Truncation of the carboxyl terminus of the G-CSF receptor, as seen in patients with acute myeloid leukemia evolving from severe congenital neutropenia, disrupted Gfi-1 up-regulation by G-CSF. Ectopic expression of a dominant negative Gfi-1 mutant, N382S, which was associated with severe congenital neutropenia, resulted in premature apoptosis and reduced proliferation of cells induced to differentiate with G-CSF. The expression of neutrophil elastase (NE) and CCAAT enhancer-binding protein epsilon (C/EBP epsilon) was significantly increased in 32D cells expressing N382S. In contrast, overexpression of wild type Gfi-1 abolished G-CSF-induced up-regulation of C/EBP epsilon but had no apparent effect on NE up-regulation by G-CSF. Notably, G-CSF-dependent proliferation and survival were inhibited upon overexpression of C/EBP epsilon but not NE. These data indicate that Gfi-1 down-regulates C/EBP epsilon expression and suggest that increased expression of C/EBP epsilon as a consequence of loss of Gfi-1 function may be deleterious to the proliferation and survival of early myeloid cells.
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