C/EBP epsilon mediates myeloid differentiation and is regulated by the CCAAT displacement protein (CDP/cut).
Neutrophils from CCAAT enhancer binding protein epsilon (C/EBP epsilon) knockout mice have morphological and biochemical features similar to those observed in patients with an extremely rare congenital disorder called neutrophil-specific secondary granule deficiency (SGD). SGD is characterized by frequent bacterial infections attributed, in part, to the lack of neutrophil secondary granule proteins (SGP). A mutation that results in loss of functional C/EBP epsilon activity has recently been described in an SGD patient, and has been postulated to be the cause of the disease in this patient. We have previously demonstrated that overexpression of CCAAT displacement protein (CDP/cut), a highly conserved transcriptional repressor of developmentally regulated genes, suppresses expression of SGP genes in 32Dcl3 cells. This phenotype resembles that observed in both C/EBP epsilon(-/-) mice and in SGD patients. Based on these observations we investigated potential interactions between C/EBP epsilon and CDP/cut during neutrophil maturation. In this study, we demonstrate that inducible expression of C/EBP epsilon in 32Dcl3/tet cells results in granulocytic differentiation. Furthermore, Northern blot analysis of G-CSF-induced CDP/cut overexpressing 32Dcl3 cells revealed absence of C/EBP epsilon mRNA. We therefore hypothesize that C/EBP epsilon positively regulates SGP gene expression, and that C/EBP epsilon is itself negatively regulated by CDP/cut during neutrophil maturation. We further demonstrate that the C/EBP epsilon promoter is regulated by CDP/cut during myeloid differentiation.
Khanna-Gupta
A
A
Section of Hematology WWW 428, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Zibello
T
T
Sun
H
H
Lekstrom-Himes
J
J
Berliner
N
N
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D018398:Homeodomain Proteins; D006801:Humans; D019891:Leukopoiesis / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; C080632:CUX1 protein, human; C000624101:Cux1 protein, mouse; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors