Notch Signaling Enhances Survival and Alters Differentiation of 32D Myeloblasts

Tan-Pertel, Hongying Tina; Walker, Liberty; Browning, Damaris; Miyamoto, Alison; Weinmaster, Gerry; Gasson, Judith C.

doi:10.4049/jimmunol.165.8.4428

Cited by 46 publications

(48 citation statements)

References 51 publications

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“…However, while several studies indicate that Notch1 is critically involved in lymphoid development (22), the role for Notch signaling in regulating the differentiation of normal hemopoietic stem cells and early progenitors along the myeloid lineage remains unclear. Recently, we have shown that the effect of activated Notch1 is to promote differentiation of the granulocytic progenitor cell line 32D (8) rather than to block differentiation or maturation of 32D cells as suggested by earlier studies (23)(24)(25)(26). Ambivalent results were also found when primary hemopoietic progenitor cells were stimulated by the Notch receptor ligands Jagged and Delta; in some studies a moderate increase in colony formation was observed (27)(28)(29)(30), whereas others saw a decrease in colony formation (31), accelerated differentiation (32), or maturation (33).…”

mentioning

confidence: 63%

Notch Signaling Induces Multilineage Myeloid Differentiation and Up-Regulates PU.1 Expression

Schroeder¹,

Kohlhof²,

Rieber³

et al. 2003

The Journal of Immunology

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Hemopoietic commitment is initiated by and depends on activation of transcription factors. However, it is unclear whether activation of lineage-affiliated transcription factors is extrinsically regulated by to date unknown agents or is the result of a cell autonomous program. Here we show that signaling by the Notch1 transmembrane receptor instructively induces myeloid differentiation of multipotent hemopoietic progenitor cells and concomitantly up-regulates the expression of the transcription factor PU.1. Transient activation of Notch1 signaling is sufficient to irreversibly reduce self-renewal of multipotent progenitor cells accompanied by increased and accelerated differentiation along the granulocyte, macrophage, and dendritic cell lineages. Activated Notch1 has no direct influence on apoptosis of multipotent progenitor cells, shows a weak inhibition of proliferation, and does not substitute for survival and proliferation signals provided by cytokines. Activated Notch1 directly increases PU.1 RNA levels, leading to a high concentration of PU.1 protein, which has been shown to direct myeloid differentiation. These findings identify Notch as an extrinsic regulator of myeloid commitment, and the lineage-affiliated transcription factor PU.1 as a specific direct target gene of Notch.

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mentioning

confidence: 63%

Notch Signaling Induces Multilineage Myeloid Differentiation and Up-Regulates PU.1 Expression

Schroeder¹,

Kohlhof²,

Rieber³

et al. 2003

The Journal of Immunology

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“…The N1⌬myc series of constructs (23), pBosHA-N1 and pBosDll3HA (24), pBosOEDN1 (25), pBos⌬EDN1 and pBosZEDN1 (26), AT-EK1 (4), mutant, and wild-type CSL reporter (JH26 and JH28, respectively) (27) constructs have been previously published. A number of constructs were kind gifts, and include the N1-Fc construct from A. Chitnis, the Hes5-luciferase reporter from R. Kageyama, and the optimized reporter construct pGL3PJH26 from M. Hancock and A. Orth.…”

Section: Methodsmentioning

confidence: 99%

Microfibrillar Proteins MAGP-1 and MAGP-2 Induce Notch1 Extracellular Domain Dissociation and Receptor Activation

Miyamoto

Lau

Hein

et al. 2006

Journal of Biological Chemistry

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113

123

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Unlike most receptors, Notch serves as both the receiver and direct transducer of signaling events. Activation can be mediated by one of five membrane-bound ligands of either the Delta-like (-1, -2, -4) or Jagged/Serrate (-1, -2) families. Alternatively, dissociation of the Notch heterodimer with consequent activation can also be mediated experimentally by calcium chelators or by mutations that destabilize the Notch1 heterodimer, such as in the human disease T cell acute lymphoblastic leukemia. Here we show that MAGP-2, a protein present on microfibrils, can also interact with the EGF-like repeats of Notch1. Co-expression of MAGP-2 with Notch1 leads to both cell surface release of the Notch1 extracellular domain and subsequent activation of Notch signaling. Moreover, we demonstrate that the C-terminal domain of MAGP-2 is required for binding and activation of Notch1. Based on the high level of homology, we predicted and further showed that MAGP-1 can also bind to Notch1, cause the release of the extracellular domain, and activate signaling. Notch1 extracellular domain release induced by MAGP-2 is dependent on formation of the Notch1 heterodimer by a furinlike cleavage, but does not require the subsequent ADAM metalloprotease cleavage necessary for production of the Notch signaling fragment. Together these results demonstrate for the first time that the microfibrillar proteins MAGP-1 and MAGP-2 can function outside of their role in elastic fibers to activate a cellular signaling pathway.Notch signaling is best known for its role in cell fate determination and is critical for regulating multiple cellular processes in many different tissues, including those of the nervous, hematopoietic, and vascular systems (1). Controlled by membrane-tethered ligands on apposing cells, ligand binding initiates canonical Notch signaling and leads to the proteolytic release of the Notch intracellular domain (NICD).2 The NICD fragment travels to the nucleus, interacts with a DNA-binding protein CSL (CBF1/Su(H)/LAG-1), and activates expression of target genes such as HES1.At least three proteolytic events are required for Notch activation through CSL. The first cleavage is ligand-independent and occurs during maturation of the co-linear Notch protein. Either during trafficking or at the cell surface, Notch is cleaved by a furin-like convertase into two fragments, the extracellular domain (N EC ) and the transmembrane-anchored intracellular domain (N TM ), that remain associated through non-covalent interactions (2-4). This "heterodimer" is the predominant form of Notch on the plasma membrane and is required for ligand-induced CSL-dependent Notch signaling (4). Accordingly, ligand engagement by the heterodimeric Notch receptor leads to sequential ADAM and ␥-secretase cleavage events that facilitate the release of NICD from its membrane tether to activate signaling (5, 6).Underscoring the importance of Notch signaling is the finding that more than 50% of T-ALL patient samples tested so far carry activating mutations of Notch1 (N1) ...

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“…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).…”

Section: Notch and Myeloid Cell Differentiationmentioning

confidence: 99%

“…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).…”

Section: Notch and Myeloid Cell Differentiationmentioning

confidence: 99%

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Notch signaling in differentiation and function of dendritic cells

Cheng

Gabrilovich

2007

Immunol Res

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Hematopoietic stem cells give rise to multiple lineages of cells. This process is governed by a tightly controlled signaling network regulated by cytokines and a direct cell-cell. Notch signaling represents one of the major pathways activated during direct interaction between hematopoietic progenitor cells and bone marrow stroma. A critical role of Notch signaling in differentiation of T and B lymphocytes has now been established. Until recently, the role of Notch signaling in the development of myeloid cells and particular dendritic cells remained unclear. In this review we discuss recent exciting findings that shed light on the critical role of Notch in differentiation and the function of dendritic cells and its impact on immune responses.

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Notch Signaling Enhances Survival and Alters Differentiation of 32D Myeloblasts

Cited by 46 publications

References 51 publications

Notch Signaling Induces Multilineage Myeloid Differentiation and Up-Regulates PU.1 Expression

Notch Signaling Induces Multilineage Myeloid Differentiation and Up-Regulates PU.1 Expression

Microfibrillar Proteins MAGP-1 and MAGP-2 Induce Notch1 Extracellular Domain Dissociation and Receptor Activation

Notch signaling in differentiation and function of dendritic cells

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