|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2431-2448
REVIEW ARTICLE
By
From The Fred Hutchinson Cancer Research Center, Seattle, WA; the
Department of Pediatrics, University of Washington School of Medicine,
Seattle, WA; and the Institut de Recerca Oncologica, Hospital Duran y
Reynals, Barcelona, Spain.
HEMATOPOIESIS IS A continuous
developmental process in which pluripotent stem cells and their progeny
make sequential cell fate decisions, producing mature blood cells of
the various lineages. The constant generation of appropriate numbers
and types of mature cells, as well as the maintenance of multipotent
progenitors, requires a complex regulatory network, many aspects of
which remain incompletely understood.1-7 Members of the
Notch family play critical roles in the determination of cell
fates and maintenance of progenitors in many developmental
systems.8-10 Given the extensive evolutionary and
phylogenetic conservation of Notch function, it is not surprising that
signaling through the Notch pathway has been implicated in the
regulation of hematopoiesis. Since the initial demonstration that
Notch1 is expressed in normal bone marrow (BM) hematopoietic
precursors,11 considerable evidence has emerged to support
a conserved role for Notch in the mediation of cell fate
decisions and self-renewal of progenitors during hematopoiesis. This
review presents an overview of the Notch signaling pathway, evidence
regarding Notch function, interactions of the Notch pathway with other
signal transduction pathways, and a model for Notch function in hematopoiesis.
During development, multipotent progenitors undergo lineage commitment
and maturation in a strict temporal and spatial pattern that reflects
the expression of different genes among originally equipotent
cells.2,3,6,12 Although many factors contribute to
differential gene expression, signaling between cells is one of the key
components of gene regulation and consequent appropriate cell fate
specification.6,13-15 The Notch family comprises a group of
highly conserved proteins that function both as cell surface receptors
and direct regulators of gene transcription.9,16-18 As
such, these molecules represent a unique conduit for signal transduction from the cell surface to the nucleus, permitting cells to
directly influence gene expression in their neighbors. In general,
Notch activation leads to transcriptional suppression of
lineage-specific genes, inhibiting differentiation in response to
inductive signals. Notch signaling limits the number of cells that
adopt a particular fate and leaves some progenitors uncommitted but
competent to adopt alternative fates.
Conservation of Notch Structure
Conservation of the Notch Signaling Pathway
Homotypic and Heterotypic Cell-Cell Interactions
Homotypic interactions: lateral inhibition.
Notch activation through homotypic interactions results in what has
been termed lateral inhibition: among a group of equipotent cells
exposed to a specific differentiation signal, a limited number will
adopt the specific cell fate, whereas adjacent cells (that express more
Notch) are inhibited from differentiating
(Fig 3A). These uncommitted
cells remain competent to respond to subsequent signals, but the
adoption of alternative fates may again be regulated by Notch. The
dosage-dependent effects of Notch during lateral signaling have been
demonstrated in chimeric flies and mice, in which cells expressing
different amounts of Notch are juxtaposed. In the prototype of lateral
signaling, the neural/epidermal cell fate decision during fly central
nervous system (CNS) development, cells expressing less
Notch adopt the primary (neuronal) fate and adjacent cells, expressing
more Notch, adopt the alternative (epidermal) fate.45
Similarly, during T-cell development, thymocytes expressing less Notch
adopt the primary
Heterotypic interactions: inductive signaling.
Notch signaling also occurs between Notch and DSL ligand expressed on
different cell types. Inductive signaling through these heterotypic
interactions is regulated primarily by ligand expression, limiting
Notch activation to those cells in direct contact with ligand-expressing cells. Interactions between Notch and DSL ligands can
also be modulated by other molecules, such as Fringe and
Wingless,49,50 and further regulated by a feedback
loop.51,52 Inductive signaling thus permits the
establishment of finely demarcated boundaries between cell types,
exemplified by dorsoventral boundary formation during fly wing margin
specification and vertebrate limb development.52-54
Diversification of Notch Function in Mammals
Defining the cellular and molecular mechanisms responsible for
differentiation and self-renewal of hematopoietic progenitors is
central to achieving a complete understanding of hematopoiesis. Hematopoietic stem cells and multipotent progenitors must continuously undergo lineage commitment, differentiation, and proliferation, while
also maintaining a pool of uncommitted progenitors to support the
production of new blood cells. Despite considerable progress, the
molecular processes that mediate cell fate specification and self-renewal of progenitors remain incompletely understood and controversial.2-7,12,65 Notch is a general regulator of
cell fate determination and interacts with a host of factors that are of known significance in hematopoiesis. The integration of Notch signaling with other cell-cell interactions, cytokine pathways and
transcriptional regulation may be a key to understanding the regulation
of hematopoiesis.
Myeloid Differentiation
Cytokine-specific effects of Notch1 and 2: The Notch Cytokine Response (NCR) region. Notch1 and 2 are both expressed in myeloid progenitors, raising the possibility that they have distinct functions in these cells. In studies to address this question, we found that, whereas either Notch1 or Notch2 is capable of inhibiting myeloid differentiation, they do so in a cytokine-specific manner: Notch1 in response to G-CSF, and Notch2 in response to GM-CSF.42 Furthermore, this cytokine specificity is associated with a previously uncharacterized region of Notch, which we have termed the Notch Cytokine Response (NCR) region (Fig 1). The Notch1 and 2 NCR regions also confer differences in subcellular localization and electrophoretic mobility, suggesting that differences in posttranslational modification of the NCR region may define specific molecular interactions. These studies provide the first evidence that different Notch orthologues may have distinct functions in the same cell type and indicate a molecular basis for those differences.
Lymphoid Differentiation: T-Cell Development
The CD4/CD8 lineage decision. Transgenic mice generated by Robey et al72 carry an activated intracellular form of Notch1 under control of the proximal Lck promoter, which permits expression of the transgene early in thymocyte development. Evaluation of thymic T-cell subsets from these mice revealed that expression of activated Notch1 results in an increase in mature CD8+ T cells and a corresponding decrease in CD4+ T cells.72 Expression of the Notch1 transgene in MHC class I-deficient mice demonstrated that Notch1 activity permits the development of CD8+ cells even in the absence of class I MHC molecules, which are normally required for differentiation to this lineage. However, expression of Notch1 was not sufficient to promote the generation of CD8+ cells in the absence of both MHC class I and II molecules, suggesting that MHC ligation is required for the developing thymocyte to receive the Notch signal at this maturational stage. Alternatively, MHC ligation may initiate a developmental program that can be modulated, but not initiated, by Notch signaling. The
B-Cell Development A number of observations provide circumstantial evidence that Notch also influences B-lymphocyte development. NF- B and
CBF1/RBP-J, which regulate expression of B-cell-specific genes,
also physically interact with Notch and participate in Notch
signaling.39-41,73-75 Transcriptional regulation by NF-B
is essential for normal B-cell development and
activation.76-79 CBF1 binds to promoters of several B-cell
genes and acts as a transcriptional regulator in B-cell immortalization
induced by Epstein-Barr virus (EBV).40,80 The recent
demonstration that Notch1 and 2 inhibit the bHLH transcription factor
E47 also supports a role for Notch in the regulation of B-cell-specific genes.81 E47 is essential for early
B-lymphocyte development, activation of the Ig heavy chain locus, and
initiation of Ig gene rearrangement. The conserved role of Notch in the
regulation of bHLH activity makes this finding particularly intriguing.
Lymphoid Malignancies Given the broad developmental role for Notch and its general function in regulating differentiation of immature cells, it is not surprising that both unregulated and ectopic expression of Notch have been implicated in oncogenesis. Although the Notch1-4 genes are located on different chromosomes, all have been mapped to regions of neoplasia-associated translocation or oncogenic viral insertion, and three have been directly associated with malignant transformation. Notch1 and 2 have been implicated in the development of T-lymphoid malignancies23,82,83 and contribute to neoplastic transformation in vitro.84 The Notch homologue now known as Notch4 was first identified as the int-3 oncogene associated with primary mouse mammary tumors.27,85 In all of these cases, the aberrations in Notch involve expression of truncated molecules lacking most or all of the extracellular domain. Similar truncated molecules have been shown to behave as constitutively active forms of Notch,31-34,86-89 suggesting that unregulated intracellular Notch activity might contribute to malignant transformation by inhibiting normal differentiation and permitting the continued proliferation of undifferentiated cells.T-cell malignancies. In a subset of T-cell acute lymphoblastic leukemias, breakpoint translocations involving the Notch1 gene predict expression of truncated intracellular Notch1 proteins that likely function as constitutively activated forms of Notch1.23 A direct association between expression of such truncated Notch1 proteins and the development of T-cell malignancies has been confirmed by Pear et al90 using a mouse transplantation model. These investigators found that mice transplanted with BM cells transduced with activated forms of Notch developed T-cell malignancies at a high frequency. Interestingly, equivalent tumorigenesis was observed for Notch constructs containing only the intracellular domain and those including the transmembrane domain, suggesting that either membrane-bound or free intracellular Notch molecules are oncogenic. This is in contrast to other reports associating malignant transformation primarily with nuclear forms of Notch. B-cell malignancies.
Notch has also been linked to B-cell malignancies induced by EBV.
Immortalization of B lymphocytes by EBV requires EBNA2, a virally
encoded transcriptional activator. EBNA2 transactivates cellular genes
through its association with the CSL protein
CBF1/RBP-J
Within the hematopoietic microenvironment a complex signaling network involving soluble and cell-bound cytokines, as well as interactions among hematopoietic cells and stromal elements, regulates differentiation and proliferation of hematopoietic progenitors.1,2,4,5,7,12,93 Although the importance of signaling through cytokine production has been established, the influence of direct cell-cell interactions among equivalent or different hematopoietic cells remains largely undefined. Notch, a molecule that mediates intercellular interactions and directly influences cell fate decisions may provide an important adjunct to other regulatory mechanisms. Expression of Notch ligands by BM and fetal liver stromal cells, thymic epithelial cells, and hematopoietic cells60,61,66,67 (and L.A.M., unpublished data) supports a role for Notch signaling through homotypic and heterotypic interactions in the hematopoietic and lymphopoietic microenvironments. Notch Ligands: DSL Proteins In Drosophila, the two Notch ligands Delta and Serrate have both distinct and overlapping functions.10,94 Multiple ligands corresponding to each of these two general classes have been identified in vertebrates, leading to a somewhat confusing nomenclature. In mammals, ligands having high homology to Delta are referred to as Delta or Delta-like (Dll), and those homologous to Serrate are called Serrate or Jagged (Table 1). DSL ligands, like Notch, are transmembrane proteins having an extracellular domain containing a variable number of EGF-like repeats. The extracellular domain also contains a conserved region unique to this family of molecules: a DSL (Delta/Serrate/Lag-2) domain that is required for Notch binding and activation.46,95 Serrate and Jagged also contain a conserved cysteine-rich region that is not present in Delta homologues. The intracellular domains of DSL proteins consist of short, diverse sequences of unknown function, but may be involved in multimerization.46,96Jagged1 and 2 Human Jagged1 was cloned from a normal BM cDNA library and is expressed by a subset of marrow stromal cells,60 indicating that it functions in the hematopoietic microenvironment. The coexpression of Jagged2 and Notch1 in the developing thymus suggests that Jagged2 is a ligand for the Notch1 receptor in this tissue.61,62 Mutant mice lacking a functional Jagged2 gene further illustrate the significance of Jagged-Notch signaling in T lymphopoiesis: these mice, in addition to other severe defects, have abnormal thymic morphology and impaired differentiation of  T cells.58
Delta-Like Molecules At least five distinct vertebrate orthologues of Drosophila Delta have been identified, including Delta-like (Dll) 1 and 3 in mice and humans.98,99 Dll1 and 3 have both overlapping and distinct patterns of expression, suggesting cooperative and specific signaling functions in several developmental processes. A complete analysis of Dll expression in hematopoietic tissues has not yet been reported, but Dll1 is expressed in BM stroma67 and spleen,62 suggesting possible roles in hematopoiesis and B-cell regulation.
Evidence regarding signal transduction after activation of Notch is derived mostly from nonhematopoietic systems. However, the fact that Notch, its ligands, and the intracellular factors that transmit Notch signals are all present in hematopoietic cells strongly implies that these signaling pathways function in hematopoiesis. The following section is provided as a guide to the known pathways with the expectation that this will prove to be the case. Notch Activation Signal transduction through the Notch pathway is initiated when the extracellular domain of Notch binds to its ligand on adjacent cells, resulting in activation of the intracellular domain (Fig 2). Several recent studies suggest a model for Notch processing and activation that involves two distinct proteolytic events: the first to generate a functional Notch receptor and the second to activate Notch in response to ligand binding. Blaumueller et al102 have demonstrated that functional Notch receptors are present on the cell surface as heterodimers, generated by proteolytic cleavage of the full-length Notch protein and reassociation of the extracellular and intracellular cleavage products through disulfide bonds. The metalloprotease-disintegrin Kuzbanian plays a role in Notch signaling103,104 and has been implicated in the processing of Drosophila Notch and mammalian Notch2.104 However, Logeat et al105 have found that a furin-like convertase is responsible for the processing of Notch1, suggesting that Kuzbanian is not an invariant part of Notch signaling. Different mechanisms may be involved in processing the different Notch orthologues, or different cell types may use distinct mechanisms, variables that could contribute to specificity of Notch signaling in mammals.Nuclear Functions for Notch Activation of the Notch receptor results in signal transduction through an intracellular pathway that culminates in transcriptional regulation. The molecular mechanisms involved have been a focus of intense research and remain controversial. Although there is increasing evidence that Notch-IC translocates to the nucleus and directly participates in transcriptional regulation, it is unclear whether nuclear translocation is required for Notch function in all systems. The observations that intracellular forms of Notch localize to the nucleus31,32,34,86,87 and physically interact with nuclear factors39,74,108 provide circumstantial evidence for Notch function in the nucleus. Using a model of mammalian myogenesis, Kopan et al34,107,109 have produced considerable substantiating evidence. Initial studies showed that activated Notch1 (Notch-IC) inhibits myogenesis by suppressing Myo-D-induced transcription of muscle-specific genes and that, whereas Notch-IC localizes to the nucleus, deletion of the nuclear localization sequences results in both loss of nuclear localization and function.34 Subsequent studies suggest the molecular mechanism involves association of Notch-IC with CBF1/RBP-J,109 translocation to the
nucleus,107 and transcriptional activation of HES (a
negative regulator of Myo-D) through binding of Notch/CBF1 to the HES-1
promoter.109 Studies by Struhl and Adachi110
and Lecourtois and Schweisguth111 provide convincing
evidence that Drosophila Notch is also cleaved upon ligand binding,
resulting in translocation and activity of Notch-IC in the nucleus. In
these experiments, transcriptional regulatory domains (either
activators or repressors) were inserted into the intracellular domain
of full-length Notch receptors. Activation of Notch by ligand binding
resulted in transcriptional activation or repression of target reporter
genes, indicating the nuclear translocation of Notch-IC.
Signal Transduction Through CSL Proteins The CSL (CBF1/RBP-J, Su(H), Lag-1)
family of transcriptional regulators represent a highly conserved
component of the Notch signaling pathway.9,10,16,17,112,113
These proteins physically interact with Notch-IC and mediate
cytoplasmic to nuclear signal transduction upon Notch
activation.35,39,109,114 Whereas it has been proposed that
CSL proteins sequestered by Notch are released and translocated to the
nucleus upon Notch activation,9,112 this model is not
entirely consistent with CSL expression patterns.113,115 As
discussed above, a model incorporating recent data involves nuclear
translocation of Notch-IC and its cooperation with CSL proteins in
transcriptional regulation. CSL proteins bind specific DNA sequences to
regulate gene expression.40,41,73,80 The primary target
genes for Su(H) in the fly are those of the Enhancer of split
(E[spl]) complex that encode basic helix-loop-helix (bHLH) transcription factors.116,117 E(spl) genes have
vertebrate counterparts, such as mammalian Hairy/Enhancer of
split (HES), that are similarly activated by the CSL
proteins CBF1/RBP-J.73,109,118 E(spl)/HES proteins
inhibit activity of other bHLH proteins, thereby suppressing transcription of lineage-specific genes. In Drosophila neurogenesis, Notch signal transduction through Su(H) and E(spl)
inhibits neuronal-specific genes of the achaete-scute
complex.119,120 This pathway is highly conserved in
mammalian neurogenesis, with signaling through Notch and
RBP-J resulting in the regulation of HES-5 and the
neuronal-specific genes Mash-1 and
NeuroD.113
CSL-Independent Signaling In addition to the Notch Su(H)/CSL E(spl)/HES
bHLH pathway, Notch signaling occurs through other pathways
that may be equally important. In the fly, only a subset of processes
mediated by Notch-Su(H) signaling require E(spl), implying divergent
pathways for transcriptional activation and repression after CSL
activation.126 Notch signaling also occurs through pathways
that do not require CSL.81,127,128 It is particularly
interesting that Notch-mediated inhibition of myogenesis in C2C12
myoblasts occurs through a mechanism that does not require either CSL
or HES,127 but in 3T3 fibroblasts and 10T1/2 cells occurs
through the CSL-HES pathway,34,118 indicating that both
CSL-dependent and CSL-independent signaling may occur in the same
developmental process.
Notch Interactions With NF- B/Rel and IB
families of transcriptional regulators may also have particular relevance to hematopoiesis. In cooperation with other transcription factors, NF-B regulates transcription of numerous genes involved in
the differentiation and activation of hematopoietic cells, including
cytokines, cytokine receptors, acute-phase reactants, and adhesion
molecules.76,78,79 The NF-B regulatory network is
particularly important in the immune response, but also plays a role in
proliferation and differentiation of hematopoietic cells, apoptosis,
and embryogenesis.77-79,132
Notch Interactions With Other Nuclear Factors Notch interactions in the nucleus are not limited to transcription factors, but also include several proteins that regulate chromatin structure. In C elegans, EMB-5 interacts with the cdc10 repeats of Glp-1 and Lin-12 and is required for signal transduction through these Notch receptors.136 EMB-5 is thought to influence gene transcription by facilitating changes in chromatin structure in response to Notch activation. Mammalian homologues of EMB-5 have been identified, but their role in Notch signaling remains to be determined.
In general, Notch activation inhibits differentiation, leaving cells competent to adopt alternative fates. However, it has become increasingly evident that superimposed on this general function are subtleties in Notch signaling that permit diverse effects, depending on the developmental stage of an individual cell and the microenvironmental context. Some of these effects are imparted by molecules that are not integral components of the Notch pathway, but that modulate Notch signal transduction (Table 1).10 These modulators include molecules that influence Notch-DSL ligand interactions (Fringe), intracellular signal transduction (Dishevelled), and intrinsic Notch signaling (Numb), as well as molecules that modulate Notch function through unknown mechanisms such as SEL-12/Presenilins.144 Fringe Drosophila Fringe145 and the mammalian Lunatic, Manic, and Radical fringe genes146 encode secreted molecules that modulate interactions of Notch with distinct ligands. For example, during dorsal-ventral boundary formation in the fly wing, Fringe specifically inhibits Serrate-Notch signaling and facilitates Delta-Notch signaling in the dorsal compartment.49,147 Lunatic fringe plays an essential role in Notch signaling and boundary formation during mammalian somitogenesis, as shown by the phenotype of knockout mice.148,149 The coincident expression of mammalian Fringe, Dll, and Jagged along boundaries of other Notch-dependent processes indicates a generally conserved role for Fringe in Notch signaling and pattern formation.146,150,151 The expression of Lunatic fringe by hematopoietic cells in the fetal liver and along the boundary between immature and mature thymocytes in the thymus further suggests that this role is conserved in the hematopoietic system.151Numb Progeny of a single cell may adopt distinct cell fates as a consequence of both extrinsic and intrinsic factors. Asymmetric cell division is a fundamental mechanism that contributes to the generation of diverse cell types.48,152 During neurogenesis in flies and mice, the asymmetric distribution of Numb inhibits Notch activity in one daughter cell, thus biasing Notch-mediated signaling.36,48,153-155 In the mouse, some cell divisions are symmetric, giving rise to equivalent progeny; in this case, Numb is equally distributed to daughter cells. Whether the cell division, and the distribution of Numb, is asymmetric or symmetric depends on whether the orientation of the mitotic spindle is horizontal or vertical. Interestingly, Notch is also asymmetrically distributed in horizontal cell divisions during mammalian neurogenesis.156 Together, these observations suggest that asymmetric distribution of Numb and/or Notch in stem cell progeny may result in differential Notch activity that establishes an initial signaling bias between otherwise equivalent progenitors.
Over the past few years the interactions of Notch with other signaling pathways have come to be recognized as an important aspect of developmental regulation.10,44,157,158 These interactions create a regulatory network that influences Notch activity as well as the effects of various inductive signals. Although the precise molecular mechanisms involved have yet to be established, recent studies have contributed important insights and have shown the complex nature of Notch interactions with other pathways. The reciprocal interactions between Notch and Ras and Notch and Wingless (Wg/Wnt) signaling reflect this complexity and have potentially important implications for Notch interactions with other regulatory pathways in hematopoiesis. Integration of Notch and Receptor Tyrosine Kinase-Ras Signaling Pathways Receptor tyrosine kinases (RTK) comprise a large family of cell surface proteins that function extensively in intercellular signaling and play an important role in hematopoiesis.159,160 Although there is considerable temporal, spatial, and functional overlap between RTK/Ras and Notch signaling in a number of developmental systems, until recently these pathways were thought to function independently. However, it is now evident that cross-talk between the two pathways occurs at a number of levels, resulting in significant interdependence and reciprocal regulation.157,161,162 In invertebrate systems, such as the Drosophila eye, appropriate specification of sequential cell fates and establishment of precise pattern formation require both inductive signals provided by RTKs and regulatory signals from Notch.10,157,162-164Integration of Notch and Wnt Signaling Pathways Members of the Wnt family, including Drosophila Wingless (Wg), C elegans lin-44, and numerous mammalian Wnt genes, encode secreted glycoproteins important for establishment of cell polarity, axis formation, and specification of cell fates during development.170,171 In mammals, Wnt signaling is emerging as an important component of a variety of developmental processes, many of which also involve Notch. Recent studies indicate that Wnt signaling plays a role in hematopoiesis,172,173 making it tempting to speculate that the two pathways interact in the hematopoietic system.Notch, Wingless, and control of cell proliferation. Interactions between Notch and Wg in the fly wing have elucidated another role for Notch in developmental regulation: the control of cell proliferation. In the wing imaginal disc, Notch induces mitotic activity and Wg acts synergistically with Notch to promote cell proliferation.179,180 In contrast, at the wing margin, Notch and Wg induce cell-cycle arrest to establish a zone of nonproliferating cells.181 These findings have important implications for the role of Notch in developmental processes, extending its role to include both differentiation and proliferation and again showing how the effects of Notch depend on the precise developmental context. Wnt signaling in hematopoiesis. A role for Wnt signaling in hematopoiesis has recently been proposed, raising the possibility that Notch and Wnt also cooperate in hematopoietic regulation. Austin et al172 have demonstrated that Wnt-5a and Wnt-10b, as well as several frizzled genes (which encode Wnt receptors171), are expressed in the murine embryonic yolk sac, fetal liver, and fetal liver AA4+ hematopoietic progenitors. Wnt-5a was specifically expressed in fetal liver stromal cells, and Wnt-10b was specifically expressed in fetal liver AA4+Sca+kit+ cells, a population enriched for hematopoietic stem/progenitor cells. Furthermore, culture of fetal liver AA4+Sca+kit+ cells in the presence of Wnt proteins promoted the expansion of multilineage progenitors, and AA4+Sca+kit+ cells transduced with Wnt-5a showed increased proliferation in vitro. Although Wnt expression was not detected in linloSca+ BM progenitors, these cells expressed frizzled genes and showed increased survival and proliferation in cultures containing Wnt proteins.
Integration of Notch With Other Signaling Pathways: Coordination of Inductive Signals In many developmental systems, the integration of inductive signals imparted by members of the EGF receptor (RTK), Wnt, transforming growth factor- (TGF-), and Hedgehog families is crucial for pattern
formation and tissue organization.158,162,176,182,183 These
signals may also cooperate to form microenvironmental niches that
permit the maintenance and proliferation of stem cells.184 The influence of Notch on signaling through these pathways, together with its role as a mediator of progenitor self-renewal and cell fate
determination in the same processes, suggests that coordination of
various inductive signals by Notch may be a common theme in developmental regulation. The integration of Fringe with Wnt, Hedgehog,
and TGF-/BMP signaling in wing and limb development further supports
a central role for Notch in these processes.54,185 TGF-
and other members of this family, including the Bone Morphogenic Proteins BMP2 and 4, are crucial for blood formation during
embryogenesis186-189; thus, it is intriguing to speculate
that Notch may function at this earliest stage of hematopoiesis to
regulate cell fate decisions induced by TGF-, BMP, and Wnt signals.
Considering the specific evidence for Notch function in hematopoiesis, as well as the interactions of Notch with factors that are of known importance in hematopoiesis, it seems very likely that Notch plays a key role in many aspects of hematopoiesis. The hematopoietic microenvironment represents a complex network of inductive signals, regulatory molecules, and cell-cell interactions that permit the simultaneous determination of various hematopoietic cell fates. The interaction of Notch with multiple components of this regulatory network may allow it to function as a master regulator, integrating various signaling pathways to limit the number of cells that respond to diverse signals. The experimental evidence confirming this role is likely to emerge over time; a model incorporating the current data might facilitate this work.
If this review makes anything clear, it should be the awesome array of interactions between Notch and other molecules that have important roles in hematopoiesis. Although the evidence allows us to speculate broadly on the role of Notch in hematopoiesis, specific information is lacking for all but a few aspects of the problem. This review raises many questions; we hope it will inspire research leading to some answers. Which of the Notch molecules, ligands, and modulators function in different hematopoietic cells at various stages of hematopoiesis? How does the Notch pathway interact with cytokine pathways, what is the molecular basis of those interactions, and what specific interactions and effects can be attributed to the different Notch molecules? How does Notch interact with other developmental pathways, especially during embryonic hematopoiesis? What is the effect of Notch on transcriptional regulation, how does Notch interact with specific transcription factors and chromatin proteins, and what genes are regulated through Notch signaling? What are the clinical implications for Notch in hematopoiesis? What role does Notch play in hematopoietic malignancies, proliferative disorders, and cytopenias? Can Notch signaling be exploited for stem cell expansion and gene therapy? Deciphering the complex interactions involving multiple Notch molecules in hematopoiesis presents a considerable challenge and should provide fertile ground for investigation for some time to come.
The authors have attempted to cite the most pertinent references. However, due to space constraints and the expanse of current literature, we could not include every appropriate reference. We apologize to any investigators who believe their work was not adequately credited and refer readers to the cited reviews for primary references. We express our appreciation to David Martin and Matt Lorincz for helpful comments on the manuscript and to the James S. McDonnell Foundation for laboratory support (L.A.M.).
Submitted October 5, 1998; accepted December 15, 1998.
Address reprint requests to Laurie A. Milner, MD, The Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, MS C3-168, PO Box 19024, Seattle, WA 98109-1024; e-mail: lmilner{at}fhcrc.org.
1. Ogawa M: Differentiation and proliferation of hematopoietic stem cells. Blood 81:2844, 1993 2. Orkin SH: Hematopoiesis: How does it happen? Curr Biol 7:870, 1995 3. Shivdasani RA, Orkin SH: The transcriptional control of hematopoiesis. Blood 87:4025, 1996 4. Metcalf D: Regulatory mechanisms controlling hematopoiesis: Principles and problems. Stem Cells 16:3, 1998 (suppl 1) 5. Morrison SJ, Uchida N, Weissman IL: The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol 11:35, 1995 6. Morrison SJ, Shah NM, Anderson DJ: Regulatory mechanisms in stem cell biology. Cell 88:287, 1997 7. Metcalf D, Enver T, Heyworth CM, Dexter TM: Controversies in hematology: Growth factors and hematopoietic cell fate. Blood 92:345, 1998 8. Fortini ME, Artavanis-Tsakonas S: Notch: Neurogenesis is only part of the picture. Cell 75:1245, 1993 9. Artavanis-Tsakonas S, Matsuno K, Fortini ME: Notch signaling. Science 268:225, 1995 10. Egan SE, St Pierre B, Leow CC: Notch receptors, partners and regulators: From conserved domains to powerful functions. Curr Top Microbiol Immunol 228:273, 1998 11. Milner LA, Kopan R, Martin DI, Bernstein ID: A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors. Blood 83:2057, 1994 12. Cross MA, Enver T: The lineage commitment of haemopoietic progenitor cells. Curr Opin Genet Dev 7:609, 1997 13. Dainiak N: Surface membrane-associated regulation of cell assembly, differentiation, and growth. Blood 78:264, 1991 14. Greenwald I, Rubin GM: Making a difference: The role of cell-cell interactions in establishing separate identities for equivalent cells. Cell 68:271, 1992 15. Zon LI: Developmental biology of hematopoiesis. Blood 86:2876, 1995 16. Kopan R, Turner DL: The Notch pathway: Democracy and aristocracy in the selection of cell fate. Curr Opin Neurobiol 6:594, 1996
17.
Honjo T:
The shortest path from the surface to the nucleus: RBP-J 18. Lewis J: A short cut to the nucleus. Nature 393:304, 1998 19. Kimble J, Simpson P: The Lin-12/Notch signaling pathway and its regulation. Annu Rev Cell Dev Biol 13:333, 1997 20. Weinmaster G, Roberts VJ, Lemke G: A homolog of Drosophila Notch expressed during mammalian development. Development 113:199, 1991 21. Franco del Amo F, Smith DE, Swiatek PJ, Gendron-Maguire M, Greenspan RJ, McMahon AP, Gridley T: Expression pattern of Motch, a mouse homolog of Drosophila Notch, suggests an important role in early postimplantation mouse development. Development 115:737, 1992 22. Kopan R, Weintraub H: Mouse Notch: Expression in hair follicles correlates with cell fate determination. J Cell Biol 121:631, 1993 23. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J: TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649, 1991 24. Weinmaster G, Roberts VJ, Lemke G: Notch2: A second mammalian Notch gene. Development 116:931, 1992
25.
Lardelli M, Lendahl U:
Motch A and Motch B 26. Lardelli M, Dahlstrand J, Lendahl U: The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech Dev 46:123, 1994 27. Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J: Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development 122:2251, 1996 28. Robey E: Notch in vertebrates. Curr Opin Genet Dev 7:551, 1997 29. Weinmaster G: Notch signaling: Direct or what? Curr Opin Genet Dev 8:436, 1998 30. Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S: Specific EGF repeats of Notch mediate interactions with Delta and Serrate: Implications for Notch as a multifunctional receptor. Cell 67:687, 1991 31. Rebay I, Fehon RG, Artavanis-Tsakonas S: Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor. Cell 74:319, 1993 32. Lieber T, Kidd S, Alcamo E, Corbin V, Young MW: Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei. Genes Dev 7:1949, 1993 33. Roehl H, Kimble J: Control of cell fate in C. elegans by a GLP-1 peptide consisting primarily of ankyrin repeats. Nature 364:632, 1993 34. Kopan R, Nye JS, Weintraub H: The intracellular domain of mouse Notch: A constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development 120:2385, 1994 35. Roehl H, Bosenberg M, Blelloch R, Kimble J: Roles of the RAM and ANK domains in signaling by the C.elegans GLP-1 receptor. EMBO J 15:7002, 1996 36. Zhong W, Feder JN, Jiang M, Jan LY, Jan YN: Asymmetric localization of a mammalian Numb homolog during mouse cortical neurogenesis. Neuron 17:43, 1996 37. Axelrod JD, Matsuno K, Artavanis-Tsakonas S, Perrimon N: Interaction between Wingless and Notch signaling pathways mediated by Dishevelled. Science 271:1826, 1996
38.
Aster JC, Robertson ES, Hasserjian RP, Turner JR, Kieff E, Sklar J:
Oncogentic forms of NOTCH1 lacking either the primary binding site for RBP-J
39.
Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T, Furukawa T, Honjo T:
Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J
40.
Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD:
Truncated mammalian Notch1 activates CBF1/RBPJ 41. Kato H, Taniguchi Y, Kurooka H, Minoguchi S, Sakai T, Nomura-Okazaki S, Tamura K, Honjo T: Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development 124:4133, 1997 42. Bigas A, Martin DIK, Milner LA: Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Mol Cell Biol 18:2324, 1998 43. Simpson P: Notch signalling in development: On equivalence groups and asymmetric developmental potential. Curr Opin Genet Dev 7:537, 1997 44. Greenwald I: LIN-12/Notch signaling: Lessons from worms and flies. Genes Dev 12:1751, 1998 45. Heitzler P, Simpson P: The choice of cell fate in the epidermis of Drosophila. Cell 64:1083, 1991 46. Muskavitch MAT: Delta-Notch signaling and Drosophila cell fate choice. Dev Biol 166:415, 1994
47.
Washburn T, Schweighoffer E, Gridley T, Chang D, Fowlkes BJ, Cado D, Robey E:
Notch activity influences the 48. Lu B, Jan LY, Jan Y: Asymmetric cell division: Lessons from flies and worms. Curr Opin Genet Dev 8:392, 1998 49. Fleming RJ, Gu Y, Hukriede NA: Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development 124:2873, 1997 50. Micchelli CA, Rulifson EJ, Blair SS: The function and regulation of cut expression on the wing margin of Drosophila: Notch, Wingless and a dominant negative role for Delta and Serrate. Development 124:1485, 1997 51. de Celis JF, Bray S: Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124:3241, 1997 52. Neumann CJ, Cohen SM: A hierarchy of cross-regulation involving Notch, wingless, vestigial and cut organizes the dorsal/ventral axis of the Drosophila wing. Development 122:3477, 1996 53. de Celis JF, Garcia-Bellido A, Bray SJ: Activation and function of Notch at the dorsal-ventral boundary of the wing imaginal disc. Development 122:369, 1996 54. Gaunt SJ: Chick limbs, fly wings and homology at the fringe. Nature 386:324, 1997 55. Swiatek PJ, Lindsell CE, del Amo FF, Weinmaster G, Gridley T: Notch1 is essential for postimplantation development in mice. Genes Dev 8:707, 1994 56. Conlon RA, Reaume AG, Rossant J: Notch1 is required for the coordinate segmentation of somites. Development 121:1533, 1995 57. Gridley T: Notch signaling in mice, in Notch/Lin-12 Signalling. Proceedings from the Instituto Juan March de Estudios e Investigaciones, vol 78. Madrid, Spain, Centro de Reuniones Internacionales Sobre Biologia, 1998, p 24. 58. Jiang R, Lan Y, Chapman HD, Shawber C, Norton CR, Serreze DV, Weinmaster G, Gridley T: Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev 12:1046, 1998 59. Hrabe de Angelis M, McIntyre J II, Gossler A: Maintenance of somite borders in mice requires the Delta homologue Dll1. Nature 386:717, 1997 60. Li L, Milner LA, Deng Y, Iwata M, Banta A, Graf L, Marcovina S, Friedman C, Trask B, Hood L, Torok-Storb B: The human homolog of rat Jagged, hJagged1, is expressed by marrow stroma and inhibits differentiation of 32D cells through interaction with Notch1. Immunity 8:43, 1998 61. Shawber C, Boulter J, Lindsell CE, Weinmaster G: Jagged2: A Serrate-like gene expressed during rat embryogenesis. Dev Biol 180:370, 1996 62. Luo B, Aster JC, Hasserjian RP, Kuo F, Sklar J: Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Mol Cell Biol 17:6057, 1997 63. Mitsiadis TA, Lardelli M, Lendahl U, Thesleff I: Expression of Notch1,2, and 3 is regulated by epithelial-mesenchymal interactions and retinoic acid in the developing mouse tooth and associated with determination of ameloblast cell fate. J Cell Biol 130:407, 1995 64. Lindsell CE, Boulter J, diSibio G, Gossler A, Weinmaster G: Expression patterns of Jagged, Delta1, Notch1, Notch2 and Notch3 genes identify ligand-receptor pairs that may function in neural development. Mol Cell Neurosci 8:14, 1996 65. Socolovsky M, Lodish HF, Daley GQ: Control of hematopoietic differentiation: Lack of specificity in signaling by cytokine receptors. Proc Natl Acad Sci USA 95:6573, 1998 66. Varnum-Finney B, Purton LE, Yu M, Brashem-Stein C, Flowers D, Staats S, Moore KA, Le Roux I, Mann R, Gray G, Artavanis-Tsakonas S, Bernstein ID: The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91:4084, 1998 67. Jones P, May G, Healy L, Brown J, Hoyne G, Delassus S, Enver T: Stromal expression of Jagged1 promotes colony formation by fetal hematopoietic progenitor cells. Blood 92:1505, 1998 68. Milner LA, Bigas A, Kopan R, Brashem-Stein C, Black M, Bernstein ID, Martin DIK: Inhibition of granulocytic differentiation by mNotch1. Proc Natl Acad Sci USA 93:13014, 1996 69. Migliaccio G, Migliaccio AR, Kreider BL, Rovera G, Adamson JW: Selection of lineage-restricted cell lines immortalized at different stages of hematopoietic differentiation from the murine cell line 32D. J Cell Biol 109:833, 1989 70. von Boehmer H: T-cell development: Is Notch a key player in lineage decisions? Curr Biol 7:R308, 1997 71. Hasserjian RP, Aster JC, Davi F, Weinberg DS, Sklar J: Modulated expression of Notch1 during thymocyte development. Blood 88:970, 1996 72. Robey E, Chang D, Itano A, Cado D, Alexander H, Lans D, Weinmaster G, Salmon P: An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell 87:483, 1996 73. Hsieh JJ-D, Nofziger DE, Weinmaster G, Hayward SD: Epstein-Barr virus immortalization: Notch2 interacts with CBF1 and blocks differentiation. J Virol 71:1938, 1997
74.
Guan E, Wang J, Laborda J, Norcross M, Baeuerle PA, Hoffman T:
T cell leukemia-associated human Notch/TAN-1 has I
75.
Oswald F, Liptay S, Adler G, Schmid RM:
NF-
76.
Siebenlist U, Franzoso G, Brown K:
Structure, regulation, and function of NF- 77. Baeuerle PA, Henkel T: Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12:141, 1994
78.
Baeuerle P, Baltimore D:
NF-
79.
Baldwin ASJ:
The NF-
80.
Henkel T, Ling PD, Hayward SD, Peterson MG:
Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J 81. Ordentlich P, Lin A, Shen C, Blaumueller C, Matsuno K, Artavanis-Tsakonas S, Kadesch T: Notch inhibition of E47 supports the existence of a novel signaling pathway. Mol Cell Biol 18:2230, 1998 82. Rohn JL, Lauring AS, Linenberger ML, Overbaugh J: Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma. J Virol 70:8071, 1996 83. Girard L, Hanna Z, Beaulieu N, Hoemann CD, Simard C, Kozak CA, Jolicoeur P: Frequent provirus insertional mutagenesis of Notch1 in thymomas of MMTVD/myc transgeneic mice suggests a collaboration of c-myc and Notch1 for oncogenesis. Genes Dev 10:1930, 1996 84. Capobianco AJ, Zagouras P, Blaumueller CM, Artavanis-Tsakonas S, Bishop JM: Neoplastic transformation by truncated alleles of human Notch1/TAN1 and Notch2. Mol Cell Biol 17:6265, 1997 85. Robbins J, Blondel BJ, Gallahan D, Callahan R: Mouse mammary tumor gene int-3: A member of the Notch gene family transforms mammary epithelial cells. J Virol 66:2594, 1992 86. Fortini ME, Rebay I, Caron LA, Artavanis-Tsakonas S: An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye. Nature 365:555, 1993 87. Struhl G, Fitzgerald K, Greenwald I: Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo. Cell 74:331, 1993 88. Coffman CR, Skoglund P, Harris WA, Kintner CR: Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus embryos. Cell 73:659, 1993 89. Nye JS, Kopan R, Axel R: An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells. Development 120:2421, 1994 90. Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J, Baltimore D: Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 183:2283, 1996 91. Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S: Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci USA 92:6414, 1995 92. Liu Y, Dehni G, Purcell KJ, Sokolow J, Carcangiu ML, Artavanis-Tsakonas S, Stifani S: Epithelial expression and chromosomal location of human TLE genes: Implications for Notch signaling and neoplasia. Genomics 31:58, 1996 93. Lemischka IR: Microenvironmental regulation of hematopoietic stem cells. Stem Cells 15:63, 1997 (suppl 1) 94. Fleming RJ, Purcell K, Artavanis-Tsakonas S: The NOTCH receptor and its ligands. Trends Cell Biol 7:437, 1997 95. Fitzgerald K, Greenwald I: Interchangeability of Caenorhabditis elegans DSL proteins and intrinsic signalling activity of their extracellular domains in vivo. Development 121:4275, 1995 96. Sun X, Artavanis-Tsakonas S: The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands. Development 122:2465, 1996 97. Roecklein BA, Torok-Storb B: Functionally distinct human marrow stromal cell lines immortalized by transduction with the human Papilloma virus E6/E7 genes. Blood 85:1005, 1995 98. Bettenhausen B, Hrabe de Angelis M, Simon D, Guenet J, Gossler A: Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development 121:2407, 1995 99. Dunwoodie SL, Henrique D, Harrison SM, Beddington RSP: Mouse Dll3: A novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 124:3065, 1997 100. Moore KA, Ema H, Lemischka IR: In vitro maintenance of highly purified, transplantable hematopoietic stem cells. Blood 89:4337, 1997 101. Moore KA, Pytowski B, Witte L, Hicklin D, Lemischka IR: Hematopoietic activity of a stromal cell transmembrane protein containing epidermal growth factor-like repeat motifs. Proc Natl Acad Sci USA 94:4011, 1997 102. Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S: Intracellular cleavage of notch leads to a heterodimeric receptor on the plasma membrane. Cell 90:281, 1997 103. Sotillos S, Roch F, Campuzano S: The metalloprotease-disintegrin Kuzbanian participates in Notch activation during growth and patterning of Drosophila imaginal discs. Development 124:4769, 1997 104. Pan D, Rubin GM: Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 90:271, 1997 105. Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israel A: The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA 95:8108, 1998 106. Kopan R, Schroeter EH, Weintraub H, Nye J: Signal transduction by activated mNotch: Importance of proteolytic processing and its regulation by the extracellular domain. Proc Natl Acad Sci USA 93:1683, 1996 107. Schroeter EH, Kisslinger JA, Kopan R: Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393:382, 1998 108. Aster J, Pear W, Hasserjian R, Davi F, Luo B, Scott M, Baltimore D, Sklar J: Functional analysis of the TAN-1 gene, a human homolog of Drosophila Notch. Cold Spring Harb Symp Quant Biol 59:125, 1994 109. Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A: Signalling downstream of activated mammalian Notch. Nature 377:355, 1995 110. Struhl G, Adachi A: Nuclear access and action of Notch in vivo. Cell 93:649, 1998 111. Lecourtois M, Schweisguth F: Indirect evidence for Delta-dependent intracellular processing of Notch in Drosophila embryos. Curr Biol 8:771, 1998 112. Fortini ME, Artavanis-Tsakonas S: The suppressor of Hairless protein participates in Notch receptor signaling. Cell 79:273, 1994 113. de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, Conlon RA: Conservation of the Notch signaling pathway in mammalian neurogenesis. Development 124:1139, 1997 114. Lu FM, Lux SE: Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1-responsive element. Proc Natl Acad Sci USA 93:5663, 1996 115. Gho M, Lecourtois M, Geraud G, Posakony JW, Schweisguth F: Subcellular localization of Suppressor of Hairless in Drosophila sense organ cells during Notch signaling. Development 122:1673, 1996 116. Lecourtois M, Schweisguth F: The neurogenic Suppressor of Hairless DNA-binding protein mediates the transcriptional activation of the Enhancer of split complex genes triggered by Notch signaling. Genes Dev 9:2598, 1995 117. Bailey AM, Posakony JW: Suppressor of Hairless directly activates transcription of Enhancer of split complex genes in response to Notch receptor activity. Genes Dev 9:2609, 1995 118. Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S: Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev 6:2620, 1992 119. Martin-Bermudo MD, Carmena A, Jimenez F: Neurogenic genes control gene expression at the transcriptional level in early neurogenesis and in mesoectoderm specification. Development 121:219, 1995 120. Oellers N, Dehio M, Knust E: bHLH proteins encoded by the Enhancer of split complex of Drosophila negatively interfere with transcriptional activation mediated by proneural genes. Mol Genet 117:1113, 1994
121.
Hsieh JJ, Hayward SD:
Masking of the CBF1/RBP-J 122. Dou S, Zeng X, Cortes P, Erdjument-Bromage H, Tempst P, Honjo T, Vales LD: The recombination signal sequence-binding protein RBP-2N functions as a transcriptional repressor. Mol Cell Biol 14:3310, 1994
123.
Plaisance S, Vanden Berghe W, Boone E, Fiers W, Haegeman G:
Recombination signal sequence binding protein J
124.
Chen Y, Fischer WH, Gill GN:
Regulation of the ERBB-2 promoter by RBPJ
125.
Eastman DS, Slee R, Skoufos E, Bangalore L, Bray S, Delidakis C:
Synergy between Suppressor of Hairless and Notch in regulation of Enhancer of split m 126. de Celis JF, de Celis J, Ligoxygakis P, Preiss A, Delidakis C, Bray S: Functional relationships between Notch, Su(H) and the bHLH genes of the E(spl) complex: The E(spl) genes mediate only a subset of Notch activities during imaginal development. Development 122:2719, 1996 127. Shawber C, Nofzige D, Hsieh JJ-D, Lindsell C, Bogler O, Hayward D, Weinmaster G: Notch signaling inhibits muscle differentiation through a CBF1-independent pathway. Development 122:3765, 1996 128. Matsuno K, Go MJ, Sun X, Eastman DS, Artavanis-Tsakonas S: Suppressor of Hairless-independent events in Notch signaling imply novel pathway elements. Development 124:4265, 1997 129. Diederich RJ, Matsuno K, Hing H, Artavanis-Tsakonas S: Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway. Development 120:473, 1994 130. Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, Artavanis-Tsakonas S: Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development 121:2633, 1995 131. Sieweke MH, Graf T: A transcription party during blood cell differentiation. Curr Opin Genet Dev 8:545, 1998
132.
Zhang M, Sun S, Bell L, Miller BA:
NF-
133.
Liou H-C, Baltimore D:
Regulation of the NF-
134.
Gilmore TD, Morin PJ:
The I
135.
Hatada EN, Nieters A, Wulczyn FG, Naumann M, Meyer R, Nucifora G, McKeithan TW, Scheidereit C:
The ankyrin repeat domains of the NF- 136. Hubbard EJA, Dong Q, Greenwald I: Evidence for physical and functional association between EMB-5 and LIN-12 in Caenorhabditis elegans. Science 273:112, 1996 137. Smoller D, Friedel C, Schmid A, Bettler D, Lam L, Yedvobnick B: The Drosophila neurogenic locus mastermind encodes a nuclear protein unusually rich in amino acid homopolymers. Genes Dev 4:1688, 1990 138. Paroush Z, Finley RLJ, Kidd T, Wainwright SM, Ingham PW, Brent R, Ish-Horowicz D: Groucho is required for Drosophila neurogenesis, segmentation and sex-determination, and interacts directly with Hairy-related bHLH proteins. Cell 79:805, 1994 139. Bettler D, Pearson S, Yedvobnick B: The Nuclear protein encoded by the Drosophila neurogenic gene mastermind is widely expressed and associates with specific chromosomal regions. Genetics 143:859, 1996 140. Stifani S, Blaumueller CM, Redhead NJ, Hill RE, Artavanis-Tsakonas S: Human homologs of a Drosophila Enhancer of split gene product define a novel family of nuclear proteins. Nat Genet 2:119, 1992 141. Jimenez G, Paroush Z, Ish-Horowicz D: Groucho acts as a corepressor for a subset of negative regulators, including Hairy and Engrailed. Genes Dev 11:3072, 1997 142. Fisher AL, Caudy M: Groucho proteins: Transcriptional corepressors for specific subsets of DNA-binding transcription factors in vertebrates and invertebrates. Genes Dev 12:1931, 1998 143. Palaparti A, Baratz A, Stifani S: The Groucho/Transducin-like enhancer of split transcriptional repressors interact with the genetically defined amino-terminal silencing domain of Histone H3. J Biol Chem 42:26604, 1997 144. Levitan D, Greenwald I: Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 377:351, 1995 145. Irvine KD, Wieschaus E: Fringe, a boundary-specific molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell 79:595, 1994 146. Johnston SH, Rauskolb C, Wilson R, Prabhakaran B, Irvine KD, Vogt TF: A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway. Development 124:2245, 1997 147. Panin VM, Papayannopoulos V, Wilson R, Irvine KD: Fringe modulates Notch-ligand interactions. Nature 387:908, 1997 148. Zhang N, Gridley T: Defects in somite formation in lunatic fringe-deficient mice. Nature 394:374, 1998 149. Evrard YA, Lun Y, Aulehla A, Gan L, Johnson RL: lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394:377, 1998 150. Laufer E, Dahn R, Orozco OE, Yeo C, Pisenti J, Henrique D, Abbott UK, Fallon JF, Tabin C: Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature 386:366, 1997 151. Cohen B, Bashirullah A, Dagnino L, Campbell C, Fisher WW, Leow CC, Whiting E, Ryan D, Zinyk D, Boulianne G, Hui C, Gallie B, Phillips RA, Lipshitz HD, Egan SE: Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila. Nat Genet 16:283, 1997 152. Lin H, Schagat T: Neuroblasts: A model for the asymmetric division of stem cells. Trends Genet 13:33, 1997 153. Guo M, Jan LY, Jan YN: Control of daughter cell fates during asymmetric division: Interaction of Numb and Notch. Neuron 17:27, 1996 154. Spana EP, Doe CQ: Numb antagonizes Notch signaling to specify sibling neuron cell fates. Neuron 17:21, 1996 155. Frise E, Knoblich JA, Younger-Shepherd S, Jan LY, Jan YN: The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proc Natl Acad Sci USA 93:11925, 1996 156. Chenn A, McConnell SK: Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82:631, 1995 157. Duffy JB, Perrimon N: Recent advances in understanding signal transduction pathways in worms and flies. Curr Opin Cell Biol 8:231, 1996 158. Kim SK, Fraser SE: Pattern formation and developmental mechanisms: Converging views of diverging pathways. Curr Opin Genet Dev 8:383, 1998 159. van der Geer P, Hunter T, Lindberg RA: Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 10:251, 1994 160. Watowich SS, Wu H, Socolovsky M, Klingmuller U, Constantinescu SN, Lodish HF: Cytokine receptor signal transduction and the control of hematopoietic cell development. Annu Rev Cell Dev Biol 12:91, 1996 161. Price JV, Savenye ED, Lum D, Breitkreutz A: Dominant enhancers of Egfr in Drosophila melanogaster: Genetic links between the Notch and Egfr signaling pathways. Genetics 147:1139, 1997 162. Freeman M: Complexity of EGF receptor signalling revealed in Drosophila. Curr Opin Genet Dev 8:407, 1998 163. Freeman M: Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87:651, 1996 164. Cagan RL, Ready DF: Notch is required for successive cell decisions in the developing Drosophila retina. Genes Dev 3:1099, 1989 165. Wasserman DA, Therrien M, Rubin GM: The Ras signaling pathway in Drosophila. Curr Opin Genet Dev 5:44, 1995 166. Treisman R: Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol 8:205, 1996 167. Kuriyama M, Harada N, Kuroda S, Yamamoto T, Nakafuku M, Iwamatsu A, Yamamoto D, Prasad R, Croce C, Canaani E, Kaibuchi K: Identification of AF-6 and Canoe as putative targets for Ras. J Biol Chem 271:607, 1996 168. Matsuo T, Takahashi K, Kondo S, Kaibuchi K, Yamamoto D: Regulation of cone formation by Canoe and Ras in the developing Drosophila eye. Development 124:2671, 1997 169. Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O: Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol 13:369, 1995 170. Nusse R, Varmus HE: Wnt genes. Cell 69:1073, 1992 171. Cadigan KM, Nusse R: Wnt signaling: A common theme in animal development. Genes Dev 11:3286, 1997 172. Austin TW, Solar GP, Ziegler FC, Liem L, Matthews W: A role for the Wnt gene family in hematopoiesis: Expansion of multilineage progenitor cells. Blood 89:3624, 1997 173. Van Den Berg DJ, Sharma AK, Bruno E, Hoffman R: Role of members of the Wnt gene family in human hematopoiesis. Blood 92:3189, 1998 174. Couso JP, Martinez Arias A: Notch is required for wingless signaling in the epidermis of Drosophila. Cell 79:259, 1994 175. Blair SS: Notch and Wingless signals collide. Science 271:1822, 1996 176. Johnson RL, Tabin CJ: Molecular models for vertebrate limb development. Cell 90:979, 1997 177. Klingensmith J, Nusse R, Perrimon N: The Drosophila segment polarity gene dishevelled encodes a novel protein required for response to the wingless signal. Genes Dev 8:118, 1994 178. Theisen H, Purcell J, Bennett M, Kansagara D, Syed A, Marsh JL: dishevelled is required during wingless signaling to establish both cell polarity and cell identity. Development 120:347, 1994 179. Go MJ, Eastman DS, Artavanis-Tsakonas S: Cell proliferation control by Notch signaling in Drosophila development. Development 125:2031, 1998 180. Speicher SA, Thomas U, Hinz U, Knust E: The Serrate locus of Drosophila and its role in morphogenesis of the wing imaginal discs: Control of cell proliferation. Development 120:535, 1994 181. Johnston LA, Edgar BA: Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature 394:82, 1998 182. Hogan BL: Bone morphogenic proteins in development. Curr Opin Genet Dev 6:432, 1996 183. Baylies MK, Bate M, Gomez MR: Myogenesis: A view from Drosophila. Cell 93:921, 1998 184. Spradling AC, Xie T: decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary. Cell 94:251, 1998 185. Wu JY, Wen L, Zhang W, Rao Y: The secreted product of Xenopus gene lunatic Fringe, a vertebrate signaling molecule. Science 273:355, 1996
186.
Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ:
Defective haematopoiesis and vasculogenesis in transforming growth factor- 187. Zhang C, Evans T: BMP-like signals are required after the midblastula transition for blood cell development. Dev Genet 18:267, 1996 188. Dzierzak E, Medvinsky A: Mouse embryonic hematopoiesis. Trends Genet 11:359, 1995 189. Mead PE, Zon LI: Molecular insights into early hematopoiesis. Curr Opin Hematol 5:156, 1998
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  Z. Zhang, B. Zeng, Z. Zhang, G. Jiao, H. Li, Z. Jing, J. Ouyang, X. Yuan, L. Chai, Y. Che, et al. Suppressor of Cytokine Signaling 3 Promotes Bone Marrow Cells to Differentiate into CD8+ T Lymphocytes in Lung Tissue via Up-Regulating Notch1 Expression Cancer Res., February 15, 2009; 69(4): 1578 - 1586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Bolos, J. Grego-Bessa, and J. L. de la Pompa Notch Signaling in Development and Cancer Endocr. Rev., May 1, 2007; 28(3): 339 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Ma, M. J. Renda, L. Wang, E.-c. Cheng, C. Niu, S. W. Morris, A. S. Chi, and D. S. Krause Rbm15 Modulates Notch-Induced Transcriptional Activation and Affects Myeloid Differentiation Mol. Cell. Biol., April 15, 2007; 27(8): 3056 - 3064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. A. Mikkola and S. H. Orkin The journey of developing hematopoietic stem cells. Development, October 1, 2006; 133(19): 3733 - 3744. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Priceputu, I. Bouallaga, Y. Zhang, X. Li, P. Chrobak, Z. S. Hanna, J. Poudrier, D. G. Kay, and P. Jolicoeur Structurally Distinct Ligand-Binding or Ligand-Independent Notch1 Mutants Are Leukemogenic but Affect Thymocyte Development, Apoptosis, and Metastasis Differently J. Immunol., August 15, 2006; 177(4): 2153 - 2166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-M. Zhu, W.-L. Zhao, J.-F. Fu, J.-Y. Shi, Q. Pan, J. Hu, X.-D. Gao, B. Chen, J.-M. Li, S.-M. Xiong, et al. NOTCH1 Mutations in T-Cell Acute Lymphoblastic Leukemia: Prognostic Significance and Implication in Multifactorial Leukemogenesis. Clin. Cancer Res., May 15, 2006; 12(10): 3043 - 3049. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Monsalve, M. A. Perez, A. Rubio, M. J. Ruiz-Hidalgo, V. Baladron, J. J. Garcia-Ramirez, J. C. Gomez, J. Laborda, and M. J. M. Diaz-Guerra Notch-1 Up-Regulation and Signaling following Macrophage Activation Modulates Gene Expression Patterns Known to Affect Antigen-Presenting Capacity and Cytotoxic Activity J. Immunol., May 1, 2006; 176(9): 5362 - 5373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. G. Leong and A. Karsan Recent insights into the role of Notch signaling in tumorigenesis Blood, March 15, 2006; 107(6): 2223 - 2233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. De Smedt, I. Hoebeke, K. Reynvoet, G. Leclercq, and J. Plum Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment Blood, November 15, 2005; 106(10): 3498 - 3506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hoshino, N. Katayama, T. Shibasaki, K. Ohishi, J. Nishioka, M. Masuya, Y. Miyahara, M. Hayashida, D. Shimomura, T. Kato, et al. A novel role for Notch ligand Delta-1 as a regulator of human Langerhans cell development from blood monocytes J. Leukoc. Biol., October 1, 2005; 78(4): 921 - 929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Sarmento, H. Huang, A. Limon, W. Gordon, J. Fernandes, M. J. Tavares, L. Miele, A. A. Cardoso, M. Classon, and N. Carlesso Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation J. Exp. Med., July 5, 2005; 202(1): 157 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Takeuchi, Y. Adachi, and Y. Ohtsuki Skeletrophin, a Novel Ubiquitin Ligase to the Intracellular Region of Jagged-2, Is Aberrantly Expressed in Multiple Myeloma Am. J. Pathol., June 1, 2005; 166(6): 1817 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. K. Hadland, S. S. Huppert, J. Kanungo, Y. Xue, R. Jiang, T. Gridley, R. A. Conlon, A. M. Cheng, R. Kopan, and G. D. Longmore A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development Blood, November 15, 2004; 104(10): 3097 - 3105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Tanimizu and A. Miyajima Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors J. Cell Sci., July 1, 2004; 117(15): 3165 - 3174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Iwata, N. Awaya, L. Graf, C. Kahl, and B. Torok-Storb Human marrow stromal cells activate monocytes to secrete osteopontin, which down-regulates Notch1 gene expression in CD34+ cells Blood, June 15, 2004; 103(12): 4496 - 4502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Milner Notch signaling: a key to the pathogenesis of multiple myeloma? Blood, May 1, 2004; 103(9): 3253 - 3254. [Full Text] [PDF]
|
|
|
|
|
|
Y. Nefedova, P. Cheng, M. Alsina, W. S. Dalton, and D. I. Gabrilovich Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines Blood, May 1, 2004; 103(9): 3503 - 3510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Jundt, K. S. Probsting, I. Anagnostopoulos, G. Muehlinghaus, M. Chatterjee, S. Mathas, R. C. Bargou, R. Manz, H. Stein, and B. Dorken Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells Blood, May 1, 2004; 103(9): 3511 - 3515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Vas, L. Szilagyi, K. Paloczi, and F. Uher Soluble Jagged-1 is able to inhibit the function of its multivalent form to induce hematopoietic stem cell self-renewal in a surrogate in vitro assay J. Leukoc. Biol., April 1, 2004; 75(4): 714 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Jensen, E. I. Jauho, E. Santoni-Rugiu, U. Holmskov, B. Teisner, N. Tygstrup, and H. C. Bisgaard Transit-Amplifying Ductular (Oval) Cells and Their Hepatocytic Progeny Are Characterized by a Novel and Distinctive Expression of Delta-Like Protein/Preadipocyte Factor 1/Fetal Antigen 1 Am. J. Pathol., April 1, 2004; 164(4): 1347 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chu and E. H. Bresnick Evidence That C Promoter-binding Factor 1 Binding Is Required for Notch-1-mediated Repression of Activator Protein-1 J. Biol. Chem., March 26, 2004; 279(13): 12337 - 12345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Duan, F.-Q. Li, J. Wechsler, K. Meade-White, K. Williams, K. F. Benson, and M. Horwitz A Novel Notch Protein, N2N, Targeted by Neutrophil Elastase and Implicated in Hereditary Neutropenia Mol. Cell. Biol., January 1, 2004; 24(1): 58 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Hoyne Notch signaling in the immune system J. Leukoc. Biol., December 1, 2003; 74(6): 971 - 981. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Vigouroux, E. Yvon, H.-J. Wagner, E. Biagi, G. Dotti, U. Sili, C. Lira, C. M. Rooney, and M. K. Brenner Induction of Antigen-Specific Regulatory T Cells following Overexpression of a Notch Ligand by Human B Lymphocytes J. Virol., October 15, 2003; 77(20): 10872 - 10880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Garcia-Peydro, V. G. de Yebenes, and M. L. Toribio Sustained Notch1 signaling instructs the earliest human intrathymic precursors to adopt a {gamma}{delta} T-cell fate in fetal thymus organ culture Blood, October 1, 2003; 102(7): 2444 - 2451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Palaga, L. Miele, T. E. Golde, and B. A. Osborne TCR-Mediated Notch Signaling Regulates Proliferation and IFN-{gamma} Production in Peripheral T Cells J. Immunol., September 15, 2003; 171(6): 3019 - 3024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Magrangeas, V. Nasser, H. Avet-Loiseau, B. Loriod, O. Decaux, S. Granjeaud, F. Bertucci, D. Birnbaum, C. Nguyen, J.-L. Harousseau, et al. Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease Blood, June 15, 2003; 101(12): 4998 - 5006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Schroeder, H. Kohlhof, N. Rieber, and U. Just Notch Signaling Induces Multilineage Myeloid Differentiation and Up-Regulates PU.1 Expression J. Immunol., June 1, 2003; 170(11): 5538 - 5548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamada, H. Yamazaki, T. Yamane, M. Yoshino, H. Okuyama, M. Tsuneto, T. Kurino, S.-I. Hayashi, and S. Sakano Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells Blood, March 15, 2003; 101(6): 2227 - 2234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Golde and C. B. Eckman Physiologic and Pathologic Events Mediated by Intramembranous and Juxtamembranous Proteolysis Sci. Signal., March 4, 2003; 2003(172): re4 - re4. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Ascano, L. J. Beverly, and A. J. Capobianco The C-terminal PDZ-Ligand of JAGGED1 Is Essential for Cellular Transformation J. Biol. Chem., February 28, 2003; 278(10): 8771 - 8779. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Lebestky, S.-H. Jung, and U. Banerjee A Serrate-expressing signaling center controls Drosophila hematopoiesis Genes & Dev., February 1, 2003; 17(3): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Espinosa, J. Ingles-Esteve, A. Robert-Moreno, and A. Bigas Ikappa Balpha and p65 Regulate the Cytoplasmic Shuttling of Nuclear Corepressors: Cross-talk between Notch and NFkappa B Pathways Mol. Biol. Cell, February 1, 2003; 14(2): 491 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Akashi, X. He, J. Chen, H. Iwasaki, C. Niu, B. Steenhard, J. Zhang, J. Haug, and L. Li Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis Blood, January 15, 2003; 101(2): 383 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-E. Lin, T. Oyama, T. Nagase, K. Harigaya, and M. Kitagawa Identification of New Human Mastermind Proteins Defines a Family That Consists of Positive Regulators for Notch Signaling J. Biol. Chem., December 20, 2002; 277(52): 50612 - 50620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dorsch, G. Zheng, D. Yowe, P. Rao, Y. Wang, Q. Shen, C. Murphy, X. Xiong, Q. Shi, J.-C. Gutierrez-Ramos, et al. Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease Blood, August 28, 2002; 100(6): 2046 - 2055. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Smith, J. T. Myers, C. E. Rogers, L. Zhou, B. Petryniak, D. J. Becker, J. W. Homeister, and J. B. Lowe Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus J. Cell Biol., August 19, 2002; 158(4): 801 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Wang, A. H. Campos, C. Z. Prince, Y. Mou, and M. J. Pollman Coordinate Notch3-Hairy-related Transcription Factor Pathway Regulation in Response to Arterial Injury. MEDIATOR ROLE OF PLATELET-DERIVED GROWTH FACTOR AND ERK J. Biol. Chem., June 21, 2002; 277(26): 23165 - 23171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Wang, C. Z. Prince, Y. Mou, and M. J. Pollman Notch3 Signaling in Vascular Smooth Muscle Cells Induces c-FLIP Expression via ERK/MAPK Activation. RESISTANCE TO Fas LIGAND-INDUCED APOPTOSIS J. Biol. Chem., June 7, 2002; 277(24): 21723 - 21729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Jeffries, D. J. Robbins, and A. J. Capobianco Characterization of a High-Molecular-Weight Notch Complex in the Nucleus of Notchic-Transformed RKE Cells and in a Human T-Cell Leukemia Cell Line Mol. Cell. Biol., June 1, 2002; 22(11): 3927 - 3941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Han, K. Tanigaki, N. Yamamoto, K. Kuroda, M. Yoshimoto, T. Nakahata, K. Ikuta, and T. Honjo Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision Int. Immunol., June 1, 2002; 14(6): 637 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Jundt, I. Anagnostopoulos, R. Forster, S. Mathas, H. Stein, and B. Dorken Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma Blood, May 1, 2002; 99(9): 3398 - 3403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. G. Leong, X. Hu, L. Li, M. Noseda, B. Larrivee, C. Hull, L. Hood, F. Wong, and A. Karsan Activated Notch4 Inhibits Angiogenesis: Role of {beta}1-Integrin Activation Mol. Cell. Biol., April 15, 2002; 22(8): 2830 - 2841. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Stier, T. Cheng, D. Dombkowski, N. Carlesso, and D. T. Scadden Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome Blood, April 1, 2002; 99(7): 2369 - 2378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kopan Notch: a membrane-bound transcription factor J. Cell Sci., March 15, 2002; 115(6): 1095 - 1097. [Full Text] [PDF]
|
|
|
|
|
|
L. Espinosa, S. Santos, J. Ingles-Esteve, P. Munoz-Canoves, and A. Bigas p65-NF{kappa}B synergizes with Notch to activate transcription by triggering cytoplasmic translocation of the nuclear receptor corepressor N-CoR J. Cell Sci., March 15, 2002; 115(6): 1295 - 1303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Chu, S. Jeffries, J. E. Norton, A. J. Capobianco, and E. H. Bresnick Repression of Activator Protein-1-mediated Transcriptional Activation by the Notch-1 Intracellular Domain J. Biol. Chem., February 22, 2002; 277(9): 7587 - 7597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kumano, S. Chiba, K. Shimizu, T. Yamagata, N. Hosoya, T. Saito, T. Takahashi, Y. Hamada, and H. Hirai Notch1 inhibits differentiation of hematopoietic cells by sustaining GATA-2 expression Blood, December 1, 2001; 98(12): 3283 - 3289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Walker, A. Carlson, H. T. Tan-Pertel, G. Weinmaster, and J. Gasson The Notch Receptor and Its Ligands Are Selectively Expressed During Hematopoietic Development in the Mouse Stem Cells, November 1, 2001; 19(6): 543 - 552. [Abstract] [Full Text]
|
|
|
|
|
|
M. T. Saxena, E. H. Schroeter, J. S. Mumm, and R. Kopan Murine Notch Homologs (N1-4) Undergo Presenilin-dependent Proteolysis J. Biol. Chem., October 19, 2001; 276(43): 40268 - 40273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Cheng, A. Zlobin, V. Volgina, S. Gottipati, B. Osborne, E. J. Simel, L. Miele, and D. I. Gabrilovich Notch-1 Regulates NF-{kappa}B Activity in Hemopoietic Progenitor Cells J. Immunol., October 15, 2001; 167(8): 4458 - 4467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Jaleco, H. Neves, E. Hooijberg, P. Gameiro, N. Clode, M. Haury, D. Henrique, and L. Parreira Differential Effects of Notch Ligands Delta-1 and Jagged-1 in Human Lymphoid Differentiation J. Exp. Med., October 1, 2001; 194(7): 991 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ohishi, B. Varnum-Finney, R. E. Serda, C. Anasetti, and I. D. Bernstein The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells Blood, September 1, 2001; 98(5): 1402 - 1407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. De Vos, G. Couderc, K. Tarte, M. Jourdan, G. Requirand, M.-C. Delteil, J.-F. Rossi, N. Mechti, and B. Klein Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays Blood, August 1, 2001; 98(3): 771 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Doerfler, M. S. Shearman, and R. M. Perlmutter Presenilin-dependent gamma -secretase activity modulates thymocyte development PNAS, July 19, 2001; (2001) 161102498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Gordadze, R. Peng, J. Tan, G. Liu, R. Sutton, B. Kempkes, G. W. Bornkamm, and P. D. Ling Notch1IC Partially Replaces EBNA2 Function in B Cells Immortalized by Epstein-Barr Virus J. Virol., July 1, 2001; 75(13): 5899 - 5912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. K. Hadland, N. R. Manley, D.-m. Su, G. D. Longmore, C. L. Moore, M. S. Wolfe, E. H. Schroeter, and R. Kopan gamma -Secretase inhibitors repress thymocyte development PNAS, June 19, 2001; 98(13): 7487 - 7491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J.T. Staal, F. Weerkamp, A. W. Langerak, R. W. Hendriks, and H. C. Clevers Transcriptional Control of T Lymphocyte Differentiation Stem Cells, May 1, 2001; 19(3): 165 - 179. [Abstract] [Full Text]
|
|
|
|
|
|
F. N. Karanu, B. Murdoch, T. Miyabayashi, M. Ohno, M. Koremoto, L. Gallacher, D. Wu, A. Itoh, S. Sakano, and M. Bhatia Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells Blood, April 1, 2001; 97(7): 1960 - 1967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Morimura, S. Miyatani, D. Kitamura, and R. Goitsuka Notch Signaling Suppresses IgH Gene Expression in Chicken B Cells: Implication in Spatially Restricted Expression of Serrate2/Notch1 in the Bursa of Fabricius J. Immunol., March 1, 2001; 166(5): 3277 - 3283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bennaceur-Griscelli, C. Pondarre, V. Schiavon, W. Vainchenker, and L. Coulombel Stromal cells retard the differentiation of CD34+CD38low/neg human primitive progenitors exposed to cytokines independent of their mitotic history Blood, January 15, 2001; 97(2): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ohno, A. Izawa, M. Hattori, R. Kageyama, and T. Sudo dlk Inhibits Stem Cell Factor-Induced Colony Formation of Murine Hematopoietic Progenitors: Hes-1-Independent Effect Stem Cells, January 1, 2001; 19(1): 71 - 79. [Abstract] [Full Text]
|
|
|
|
|
|
R. Kopan and A. Goate A common enzyme connects Notch signaling and Alzheimer's disease Genes & Dev., November 15, 2000; 14(22): 2799 - 2806. [Full Text]
|
|
|
|
|
|
F. N. Karanu, B. Murdoch, L. Gallacher, D. M. Wu, M. Koremoto, S. Sakano, and M. Bhatia The Notch Ligand Jagged-1 Represents a Novel Growth Factor of Human Hematopoietic Stem Cells J. Exp. Med., November 6, 2000; 192(9): 1365 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. HOYNE, K. TAN, M. CORSIN-JIMENEZ, K. WAHL, M. STEWART, S. E. M. HOWIE, and J. R. LAMB Immunological Tolerance to Inhaled Antigen Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): S169 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bayly and D. P. LeBrun Role for Homodimerization in Growth Deregulation by E2a Fusion Proteins Mol. Cell. Biol., August 15, 2000; 20(16): 5789 - 5796. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. L. Phillips, R. E. Ernst, B. Brunk, N. Ivanova, M. A. Mahan, J. K. Deanehan, K. A. Moore, G. C. Overton, and I. R. Lemischka The Genetic Program of Hematopoietic Stem Cells Science, June 2, 2000; 288(5471): 1635 - 1640. [Abstract] [Full Text]
|
|
|
|
|
|
S. Jeffries and A. J. Capobianco Neoplastic Transformation by Notch Requires Nuclear Localization Mol. Cell. Biol., June 1, 2000; 20(11): 3928 - 3941. [Abstract] [Full Text]
|
|
|
|
|
|
K. Ohishi, B. Varnum-Finney, D. Flowers, C. Anasetti, D. Myerson, and I. D. Bernstein Monocytes express high amounts of Notch and undergo cytokine specific apoptosis following interaction with the Notch ligand, Delta-1 Blood, May 1, 2000; 95(9): 2847 - 2854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Radtke, I. Ferrero, A. Wilson, R. Lees, M. Aguet, and H. R. MacDonald Notch1 Deficiency Dissociates the Intrathymic Development of Dendritic Cells and T Cells J. Exp. Med., March 27, 2000; 191(7): 1085 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Han, Q. Ye, and M. A. S. Moore A soluble form of human Delta-like-1 inhibits differentiation of hematopoietic progenitor cells Blood, March 1, 2000; 95(5): 1616 - 1625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Facon, J.-L. Harousseau, F. Maloisel, M. Attal, J. Odriozola, A. Alegre, W. Schroyens, C. Hulin, R. Schots, P. Marin, et al. Stem Cell Factor in Combination With Filgrastim After Chemotherapy Improves Peripheral Blood Progenitor Cell Yield and Reduces Apheresis Requirements in Multiple Myeloma Patients: A Randomized, Controlled Trial Blood, August 15, 1999; 94(4): 1218 - 1225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. T. Lam, C. Ronchini, J. Norton, A. J. Capobianco, and E. H. Bresnick Suppression of Erythroid but Not Megakaryocytic Differentiation of Human K562 Erythroleukemic Cells by Notch-1 J. Biol. Chem., June 23, 2000; 275(26): 19676 - 19684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ingles-Esteve, L. Espinosa, L. A. Milner, C. Caelles, and A. Bigas Phosphorylation of Ser2078 Modulates the Notch2 Function in 32D Cell Differentiation J. Biol. Chem., November 21, 2001; 276(48): 44873 - 44880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Doerfler, M. S. Shearman, and R. M. Perlmutter Presenilin-dependent gamma -secretase activity modulates thymocyte development PNAS, July 31, 2001; 98(16): 9312 - 9317. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 1999 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
TOP
INTRODUCTION
NOTCH AS A MEDIATOR...
). Interestingly,
Notch1 is also expressed in the
CD34+lin+ subset and, at lower levels, in more
mature CD34
Two mouse Notch homologues coexpressed in a wide variety of tissues.
Exp Cell Res
204:364, 1993