Cell Cycle Arrest and Apoptosis Induced by Notch1 in B Cells

Morimura, Toshifumi; Goitsuka, Ryo; Zhang, Yong; Saito, Izumu; Reth, Michael; Kitamura, Daisuke

doi:10.1074/jbc.m006415200

Cited by 131 publications

(95 citation statements)

References 73 publications

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“…However, activation of host genes by this pathway might have important consequences for the viral replicative program. For example, in some B cell lines, Notch signaling triggers G1 arrest (and subsequent apoptosis; Morimura et al 2000). Cell cycle arrest is a common feature of herpesviral immediate-early proteins (Flemington 2001), and is thought to be beneficial to the virus by preventing cellular S phase from competing with the viral genome for essential nucleotides and other precursors.…”

Section: Discussionmentioning

confidence: 99%

The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jκ (CSL), the target of the Notch signaling pathway

et al. 2002

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The RTA protein of the Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is responsible for the switch from latency to lytic replication, a reaction essential for viral spread and KS pathogenesis. RTA is a sequence-specific transcriptional activator, but the diversity of its target sites suggests it may act via interaction with host DNA-binding proteins as well. Here we show that KSHV RTA interacts with the RBP-J protein, the primary target of the Notch signaling pathway. This interaction targets RTA to RBP-J recognition sites on DNA and results in the replacement of RBP-J 's intrinsic repressive action with activation mediated by the C-terminal domain of RTA. Mutation of such sites in target promoters strongly impairs RTA responsiveness. Similarly, such target genes are induced poorly or not at all by RTA in fibroblasts derived from RBP-J −/− mice, a defect that can be reversed by expression of RBP-J . In vitro, RTA binds to two adjacent regions of RBP-J , one of which is identical to the central repression domain that binds the Notch effector fragment. These results indicate that KSHV has evolved a ligand-independent mechanism for constitutive activation of the Notch pathway as a part of its strategy for reactivation from latency.

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Section: Discussionmentioning

confidence: 99%

The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jκ (CSL), the target of the Notch signaling pathway

et al. 2002

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“…Mouse CD40L complementary DNA cloned into a pApuro2 expression vector (a gift of Dr T. Kurosaki) was transfected into BALB / c3T3 fi broblasts (clone A31, provided by RIKEN BRC) by lipofection and puro mycin (5 μ g ml − 1 )-resistant stable clones (40L cells) were subsequently selected. Mouse BAFF cDNA cloned into a pCA-neo, a T7-tag-deleted variant of the pCAT7-neo expression vector 57 , was transfected into the 40L or 3T3 cells and G418 (2 mg ml − 1 )-resistant clones were subsequently selected. Among the 40L transfectants, a clone on which na ï ve B cells proliferated most extensively in the presence of IL-4 was named 40LB and used for the rest of the experiments.…”

Section: Methodsmentioning

confidence: 99%

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

et al. 2011

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In response to T cell-dependent antigens, B cells proliferate extensively to form germinal centres (GC), and then differentiate into memory B (B mem ) cells or long-lived plasma cells (LLPCs) by largely unknown mechanisms. Here we show a new culture system in which mouse na ï ve B cells undergo massive expansion and isotype switching, and generate GC-phenotype B (iGB) cells. The iGB cells expressing IgG1 or IgM / D, but not IgE, differentiate into B mem cells in vivo after adoptive transfer and can elicit rapid immune responses with the help of cognate T cells. Secondary culture with IL-21 maintains the proliferation of the iGB cells, while shifting their in vivo developmental fate from B mem cells to LLPCs, an outcome that can be reversed by withdrawal of IL-21 in tertiary cultures. Thus, this system enables in vitro manipulation of B-cell fate, into either B mem cells or LLPCs, and will facilitate dissection of GC-B cell differentiation programs.

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“…It was ®rst found that Notch1 or Notch2 signaling pathway inhibited the transcriptional activity of E2A/E47, an initiating transcription factor for the alternative B cell fate speci®cation, possibly through their inhibiting e ect on Ras pathway that is required for the full function of E47 (Ordentlich et al, 1998). More recently it was found that Notch1 signaling not only suppressed B cell IgH gene expression (target gene of E2A), but also induced apoptosis of chicken B cells via the upregulation of Hairy 1, and G1 cell cycle arrest through other pathways (Morimura et al, 2000(Morimura et al, , 2001. In another study, it was shown that Notch signaling also suppressed the proliferation of granulocytic progenitor 32D cells, by arresting cells in the G0/G1 phase (Schroeder and Just, 2000a), suggesting that Notch1 prevents or terminates`promiscuous trans-di erentiation' of committed T to myeloid cells.…”

Section: T Lymphocytesmentioning

confidence: 99%

Hematopoietic cytokines, transcription factors and lineage commitment

2002

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The past two decades have witnessed signi®cant advances in our understanding of the cellular physiology and molecular regulation of hematopoiesis. At the heart of stem cell self-renewal and lineage commitment decisions lies the relative expression levels of lineage-speci®c transcription factors. The expression of these transcription factors in early stem cells may be promiscuous and uctuate, but ultimately comes under the in¯uence of extracellular regulatory signals in the form of hematopoietic cytokines. In this review, we ®rst summarize our current understanding of the phenotypic characterization of hematopoietic stem cells. Next, we describe key known transcription factors which govern stem cell selfrenewal and lineage commitment decisions. Finally, we review data concerning the role of speci®c cytokines in in¯uencing these decisions. From this review, a picture emerges in which stem cell fate decisions are governed by the integrated e ects of intrinsic transcription factors and external signaling pathways initiated by regulatory cytokines.

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Cell Cycle Arrest and Apoptosis Induced by Notch1 in B Cells

Cited by 131 publications

References 73 publications

The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jκ (CSL), the target of the Notch signaling pathway

The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jκ (CSL), the target of the Notch signaling pathway

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

Hematopoietic cytokines, transcription factors and lineage commitment

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