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

Liang, Yuying; Chang, Jean; Lynch, Stephen J.; Lukac, David M.; Ganem, Don

doi:10.1101/gad.996502

Cited by 231 publications

(310 citation statements)

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“…EBNA2 and NICD are found to regulate the same cellular and viral promoters and both have been shown to be partially interchangeable in regard to activation of target genes in B-cell lines and modulation of differentiation processes, reviewed in [166]. In addition to EBV, the lytic switch protein RTA of Kaposi s sarcoma-associated herpes virus (KSHV) has been found to bind to RBP-J [172], reviewed in [173]. KSHV establishes latency in B-cells, like EBV, but can also infect endothelial cells.…”

Section: Notch and Leukemiamentioning

confidence: 99%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

584

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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Section: Notch and Leukemiamentioning

confidence: 99%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

584

499

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“…Retroviral vector expressing RBP-J was constructed by cloning RBP-J cDNA (from pcDNA3.1-RBP-J ; described in ref. 28) between BamHI and XhoI sites of retroviral vector pBMN. Recovered retrovirus was used to infect OT11 cells, and stable cells OT11-RBP-J were obtained after puromycin selection.…”

Section: Methodsmentioning

confidence: 99%

Lytic but not latent infection by Kaposi's sarcoma-associated herpesvirus requires host CSL protein, the mediator of Notch signaling

Liang

Ganem

2003

Proc. Natl. Acad. Sci. U.S.A.

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107

103

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Infection by Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) isK aposi's sarcoma (KS), the most common neoplasm of untreated AIDS patients, is a complex lesion characterized by endothelial proliferation, neoangiogenesis, and inflammatory cell infiltration (1, 2). In 1994, a novel herpesvirus, now termed KS-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), was identified in KS lesions (3), and compelling epidemiological and molecular evidence strongly links KSHV infection to KS tumorigenesis (see refs. 4 and 5 for review). Like all herpesviruses, KSHV deploys two alternative genetic programs in infection: (i) latency, in which only a handful of viral genes is expressed and no infectious progeny are produced, and (ii) lytic infection, in which most viral genes are expressed in an ordered cascade, viral DNA is amplified, and infectious virions are released. Examination of KS biopsy specimens shows that KSHV infection is localized to the tumorous endothelial (spindle) cells (6), the majority of which are latently infected (7). A small subpopulation, however, are lytically infected (7), and recent evidence suggests that both latency and lytic infection contribute importantly to KS pathogenesis. The latency program encodes numerous proteins that can affect cell survival and proliferation in vitro (8-12), whereas the lytic cycle encodes a variety of signaling proteins that can either directly mediate angiogenesis and inflammation (13-16) or induce expression of host proteins that can do likewise (17). In addition, KSHV latency is somewhat unstable, in that proliferating cells frequently give rise to uninfected segregants (A. Grundhoff and D.G., unpublished results); ongoing lytic infection also serves as a source of virus that can sustain the population of latently infected cells via de novo infection͞reinfection.In most cultured cells, the default pathway of KSHV infection is latency; that is, newly infected cells do not express the full lytic cascade, but rather maintain the viral DNA in the nucleus as a low copy number, circular episome whose expression is tightly restricted (18,19). Little is known about the mechanisms by which latency is established. Formally speaking, the absence of lytic gene expression might be due to the absence of one or more positive regulators, or to the presence of active repression (or both).A single KSHV lytic-cycle viral gene (ORF50) controls the switch from latency to lytic replication (20,21). Its product, the replication and transcription activator (RTA), is a transcription factor that is both necessary (22) and sufficient (20,22,23) to trigger lytic reactivation. The mechanisms by which KSHV RTA acts have been extensively studied in cells transiently transfected by reporter gene constructs. RTA harbors a potent C-terminal activation domain, deletion of which results in a loss of transactivation activity (22,24). In addition, it has an N-terminal DNA-binding motif that can mediate sequence-specific DNA binding, and high-affinity sites for RTA recognition have been iden...

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“…[8][9][10][11] DNA sequences similar to the consensus have been identified within the promoter regions of Notch target genes in organisms ranging from flies and worms to humans and even in the genomes of the herpesviruses, Epstein-Barr virus and Kaposi's sarcomaassociated herpesvirus. [12][13][14][15] However, more complicated arrangements of CSL binding sites have also been observed, for example the enhancer of split gene complex (E(spl)-C) in flies. 12 Certain genes of the E(spl)-C contain a unique promoter architecture, termed Su(H)-paired site (SPS), consisting of two CSL binding sites arranged in a head-to-head manner with an approximately 16 base pair A/T rich spacer sequence [ Fig.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic and structural insights into CSL‐DNA complexes

Friedmann

Kovall

2009

Protein Science

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The Notch pathway is an intercellular signaling mechanism that plays important roles in cell fates decisions throughout the developing and adult organism. Extracellular complexation of Notch receptors with ligands ultimately results in changes in gene expression, which is regulated by the nuclear effector of the pathway, CSL (C-promoter binding factor 1 (CBF-1), suppressor of hairless (Su(H)), lin-12 and glp-1 (Lag-1)). CSL is a DNA binding protein that is involved in both repression and activation of transcription from genes that are responsive to Notch signaling. One well-characterized Notch target gene is hairy and enhancer of split-1 (HES-1), which is regulated by a promoter element consisting of two CSL binding sites oriented in a head-to-head arrangement. Although previous studies have identified in vivo and consensus binding sites for CSL, and crystal structures of these complexes have been determined, to date, a quantitative description of the energetics that underlie CSL-DNA binding is unknown. Here, we provide a thermodynamic and structural analysis of the interaction between CSL and the two individual sites that comprise the HES-1 promoter element. Our comprehensive studies that analyze binding as a function of temperature, salt, and pH reveal moderate, but distinct, differences in the affinities of CSL for the two HES-1 binding sites. Similarly, our structural results indicate that overall CSL binds both DNA sites in a similar manner; however, minor changes are observed in both the conformation of CSL and DNA. Taken together, our results provide a quantitative and biophysical basis for understanding how CSL interacts with DNA sites in vivo.

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

Cited by 231 publications

References 56 publications

The Notch signaling pathway: Transcriptional regulation at Notch target genes

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Lytic but not latent infection by Kaposi's sarcoma-associated herpesvirus requires host CSL protein, the mediator of Notch signaling

Thermodynamic and structural insights into CSL‐DNA complexes

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