Notch1 Expression in Early Lymphopoiesis Influences B versus T Lineage Determination

Pui, John C.; Allman, David; Xu, Lanwei; DeRocco, Susan E.; Karnell, Fredrick G.; Bakkour, Sonia; Lee, Julia Y.; Kadesch, Tom; Hardy, Richard R.; Aster, Jon C.; Pear, Warren S.

doi:10.1016/s1074-7613(00)80105-3

Cited by 858 publications

(802 citation statements)

References 69 publications

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“…This variant was used to confirm that effects observed following MAHB expression was ITAM dependent. Both the MAHB and ITAMmutant proteins were cloned into the MIGR1 retroviral vector that expresses a bicistronic mRNA encoding either MAHB or ITAMmutant and GFP (Pui et al, 1999). The retroviral transduction efficiency for each construct was about 50%, as indicated by GFP expression (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

et al. 2005

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Immunoreceptor tyrosine-based activation motifs (ITAMs) are involved in the transduction of signals necessary for activation, differentiation, and survival in hematopoietic cells. Several viruses have been shown to encode ITAM-containing transmembrane proteins. Although expression of these viral proteins has in some cases been shown to transform nonhematopoietic cells, a causal role for a functional ITAM in this process has not been elucidated. To examine the potential transforming properties of ITAM-containing proteins, a recombinant protein consisting of ITAM-containing cytoplasmic regions of the B-cell antigen receptor was expressed in immortalized murine mammary epithelial and fibroblast cells. Mammary epithelial cells expressing this construct exhibited depolarized morphology in three-dimensional cultures. This transformed phenotype was characterized by a loss of anchorage dependence and hallmarks of epithelial to mesenchymal transition. Fibroblasts expressing this ITAM construct also lost contact inhibition and anchorage dependence. The transformed phenotype seen in both cell types was abrogated upon tyrosine to phenylalanine substitutions of the ITAMs. Inhibition of Syk tyrosine kinase, which associates with the ITAM, also prevented cell transformation. Our results indicate that expression of a nonviral ITAM-containing protein is sufficient for cell transformation. Despite lacking intrinsic enzymatic activity, ITAM-containing proteins can function as potent oncoproteins by scaffolding downstream mediators.

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Section: Resultsmentioning

confidence: 99%

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

et al. 2005

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“…These mice exhibited a complete block in T-cell development at an early stage of differentiation and an emergence of ectopic B-cell development in the thymus [134]. Conversely, overexpression of constitutive-active Notch (NICD) in the bone marrow instructed a T-cell fate in bone marrow progenitors and inhibited B-cell development [137]. The same effect was observed after overexpression of Delta4 in the thymus [138].…”

Section: T-cell Developmentmentioning

confidence: 99%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

583

499

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. The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Here, we review Notch signaling with a focus on gene regulatory events at Notch target genes. This is of utmost importance to understand Notch signaling since certain RBP-J associated cofactors and particular epigenetic marks determine the specificity of Notch target gene expression in different cell types. We subsequently summarize the current knowledge about Notch target genes and the physiological significance of Notch signaling in development and cancer.

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“…Thus, T cell development in the thymus is completely blocked in the absence of Notch1 signaling [7]. Moreover, it has been shown that ectopic expression of an activated form of Notch1 in early hematopoietic precursors results in extra-thymic T cell development in the bone marrow [8]. Recently, Schmitt and ZunigaPflücker developed a culture system whereby the T cell potential of early hematopoietic progenitors can be studied in a simple and quantitative way [9].…”

Section: Introductionmentioning

confidence: 99%

Critical role for c‐kit (CD117) in T cell lineage commitment and early thymocyte development in vitro

Massa¹,

Balc̆iūnaite²,

Ceredig³

et al. 2006

Eur J Immunol

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The precise roles played by the transmembrane receptor tyrosine kinase c-kit and its ligand stem cell factor in early T cell development are difficult to study. Using cloned Pax5-deficient progenitor B cells, we show that following Notch signaling, which induces their commitment to the T cell developmental pathway, c-kit expression is rapidly up-regulated at both the transcriptional and cell surface level. Using either an anti-c-kit monoclonal antibody or Gleevec, a pharmacological inhibitor of c-kit signaling, we show that the Notch-induced T cell differentiation of either Pax5-deficient progenitor B cells, or the equivalent cell from the bone marrow of normal mice, is strictly dependent on c-kit signaling, whereas the differentiation of normal progenitors into the B cell lineage is not. Moreover, we show that the Notch and IL-7 signalinginduced proliferation and differentiation of CD44 + CD25 -c-kit high and CD44 + CD25 + ckit high thymocytes along the T cell, but not natural killer cell or macrophage, pathway also requires c-kit signaling, whereas the Notch-induced proliferation and differentiation of CD44 -CD25 + c-kit int cells along the T cell pathway is independent of c-kit. These results further highlight the complex inter-relationships existing between c-kit, Notch and IL-7 receptor signaling that control the proliferation and differentiation of early T cell progenitors.

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Notch1 Expression in Early Lymphopoiesis Influences B versus T Lineage Determination

Cited by 858 publications

References 69 publications

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Critical role for c‐kit (CD117) in T cell lineage commitment and early thymocyte development in vitro

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