Notch1 inhibits differentiation of hematopoietic cells by sustaining GATA-2 expression

Abstract

Notch signaling is involved in cell fate decisions in many systems including hematopoiesis. It has been shown that expression of an activated form of Notch1 (aNotch1) in 32D mouse myeloid progenitor cells inhibits the granulocytic differentiation induced by granulocyte colonystimulating factor (G-CSF). Results of the current study show that aNotch1, when expressed in F5-5 mouse erythroleukemia cells, also inhibits erythroid differentiation. Comparison of the expression levels of several transcription factors after stimulation for myeloid and erythroid differentiation, in the presence or absence of aNotch1, revealed that aNotch1 did not change its regulation pattern with any of the transcription factors examined, except for GATA-2, despite its inhibitory effect on differentiation. GATA-2 was down-regulated when the parental 32D and F5-5 were induced to differentiate into granulocytic and erythroid lineages, respectively. In these induction procedures, however, the level of GATA-2 expression was sustained when aNotch1 was expressed. To ascertain whether maintenance of GATA-2 is required for the Notch-induced inhibition of differentiation, the dominant-negative form of GATA-3 (DN-GATA), which acted also against GATA-2, or transcription factor PU.1, which was recently shown to be the repressor of GATA-2, was introduced into

Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents

“…In T cells, inhibition of differentiation via suppression of pre-T-cell receptor expression has been suggested as a key mechanism of Notch-1-induced lymphomagenesis (Engel and Murre, 2002). Inhibition of differentiation may be mediated by Notch-induced helix-loop-helix inhibitory transcription factors and, in myeloid cells, by expression of GATA-2 (Kumano et al, 2001). Consistent with this multiplicity of biochemical mechanisms, different phenotypic effects are seen in different cell types.…”

Notch signaling in differentiation and function of dendritic cells

“…Most in vitro experiments have shown that active Notch-1 expands the stem cell compartment but blocks or delays terminal myeloid cell differentiation. Overexpression of constitutively active Notch-1 (ICN1) in 32D myeloid progenitor cell line inhibited granulocytic differentiation and permitted expansion of undifferentiated cells (22)(23)(24). This was probably mediated through RBP-J-Hes1 pathway since overexpression of Hes-1 had similar to ICN1 effect on 32D cell differentiation (23)(24)(25).…”

“…This was probably mediated through RBP-J-Hes1 pathway since overexpression of Hes-1 had similar to ICN1 effect on 32D cell differentiation (23)(24)(25). ICN1 inhibited erythroid differentiation of F5-5 mouse erythrolekemia cells through sustained activity of GATA2 transcription factor (24). ICN1 also blocked differentiation of human myeloid cell line HL60 to granulocytes induced by all-trans retinoic acid (ATRA) or to monocytes induced by tetradecanoylphorbol acetate (TPA) (26,27).…”

“…Overexpression of constitutively active Notch-1 (ICN1) in 32D myeloid progenitor cell line inhibited granulocytic differentiation and permitted expansion of undifferentiated cells (22)(23)(24). This was probably mediated through RBP-J-Hes1 pathway since overexpression of Hes-1 had similar to ICN1 effect on 32D cell differentiation (23)(24)(25). ICN1 inhibited erythroid differentiation of F5-5 mouse erythrolekemia cells through sustained activity of GATA2 transcription factor (24).…”

Rat limbal epithelial side population cells exhibit a distinct expression of stem cell markers that are lacking in side population cells from the central cornea

“…Specifically in the eyes, retinal SP cells have been reported to exhibit a high expression of nestin mRNA [32]. Notch 1 has also been frequently correlated to a stem cell-like phenotype, by delaying stem cell differentiation via the enhancement of self-renewal in both hematopoietic [33,34] and neural stem cells [35]. The higher expression of notch 1 observed in limbal epithelial SP cells suggests that these cells may indeed resemble other adult stem cells and may indicate a key role of notch 1 signaling in regulating ocular surface homeostasis through well-controlled corneal epithelial turnover.…”