Chapter 4 Micromanagers of Immune Cell Fate and Function

Petrocca, Fabio; Lieberman, Judy

doi:10.1016/s0065-2776(09)01204-8

Cited by 16 publications

(9 citation statements)

References 97 publications

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“…The most common approaches are based on the hypothesis that genes sharing a similar temporal profile are regulated by common transcription factors (16). In mammals, a variety of post-transcriptional regulatory mechanisms can impact mRNA kinetics following up-regulation (17), so that requiring similarity across the entire time-series may be unnecessarily restrictive. As an alternative, we propose to focus on the initial up-regulation time as a criterion to identify genes that are likely to share common regulatory control logic.…”

Section: Introductionmentioning

confidence: 99%

Antiviral Response Dictated by Choreographed Cascade of Transcription Factors

Zaslavsky¹,

Hershberg

Seto³

et al. 2010

The Journal of Immunology

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, triggers a transcriptional program that includes the production of type I IFNs. These antiviral cytokines signal in both autocrine and paracrine fashion through the JAK-STAT pathway leading to additional transcription events involving the differential expression of many hundreds of genes. The antiviral state produced by this extensive genetic reprogramming involves a core set of genes as well as pathogenspecific components (1).The DC response to individual pathogens involves multiple signals that must be integrated to initiate an appropriate immune response. Pathogenic viruses attempt to subvert normal immune function through the expression of IFN antagonists (2, 3). For example, IFN regulatory factor (IRF) 3 activation and IFN-b expression are blocked by the NS1 protein of influenza (4). Unraveling the impact of these immune antagonists would be aided by a detailed understanding of the genetic regulatory network that operates during an uninhibited antiviral response. This knowledge is lacking because previous human studies have used viruses that interfere with the immune response (4-6). One fundamental unresolved question is to what extent the antiviral response is a single interconnected transcriptional cascade (convergent architecture) or a combination of transcriptional events operating independently in reaction to the multiple signals that arise following viral insult (parallel architecture). Newcastle disease virus (NDV) infection of human DCs provides an ideal system to define the uninhibited regulatory network (7,8). NDV is an avian virus that is able to stimulate innate immunity and DC maturation, but lacks the ability to evade the human interferon response (9). By focusing on NDV, we can accurately depict the baseline network of transcription factor (TF) interactions that underlie a broad range of immune responses. Through comparative studies, this network will enable detailed analysis of other infections and greatly improve our understanding of the control mechanisms in antiviral immunity and the myriad ways through which pathogenic viruses subvert normal immune function.Systems biology methods combined with high-throughput experimental technologies are providing new insights into virus-host interactions (10, 11). Genome-wide transcriptional profiling has suggested that the DC antiviral response is characterized by temporal waves of gene activation, which may be controlled by different combinations of transcriptional regulators (1). Potential regulators can be implicated using direct approaches, such as differential expression of the TF mRNA (1) -regulatory motifs (12, 13). These methods typically provide a static view of the network. Other computational methods have been proposed to identify TFs driving time-dependent changes in expression, but these do not explicitly account for the regulation of the TF itself (14, 15). The most common approaches are based on the hypothesis that genes sharing a similar temporal profile are regulated by common TFs (16). In mammals, a variety of posttranscriptional ...

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Section: Introductionmentioning

confidence: 99%

Antiviral Response Dictated by Choreographed Cascade of Transcription Factors

Zaslavsky¹,

Hershberg

Seto³

et al. 2010

The Journal of Immunology

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“…1–3 Indeed, this unmet clinical need for the development of target specific cancer therapeutic agents have been emphasized by oncologists. Therefore, it is of paramount importance to develop novel drug delivery systems which provide superior capabilities for achieving optimal bioavailability of cytotoxic drugs at tumor sites while decreasing the systemic toxicity in tandem.…”

Section: Introductionmentioning

confidence: 99%

New nanomedicine approaches using gold–thioguanine nanoconjugates as metallo-ligands

Sleightholm

Zambre

Chanda

et al. 2011

Inorganica Chimica Acta

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Gold-thioguanine nanoconjugates (AuNP-TG) of size 3–4 nm were synthesized and the ratio between gold and 6-Thioguanine (TG) was estimated as ~1:1.5 using a cyanide digestion method and confirmed by flame atomic absorption spectroscopic analysis. AuNP-TG constructs showed high in vitro stability under different pH conditions and biologically relevant solutions for a period of 24 hours. Reaction of AuNP-TG with europium or platinum salts resulted in the formation of organized self-assembled metallo-networks.

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“…Compared to the studies on transactivation, the mechanisms involved in the negative regulation of IL-2 gene expression are less well studied. Although the roles of co-repressors and histone deacetylases in the transcriptional repression of IL-2 has been demonstrated [14], it is also becoming clear that a number of miRNAs are also involved in shaping of the immune responses [15,16] at least in part through the regulation of cytokine genes [17]. For example, miR-146a has been shown to modulate the adaptive immune responses by regulating the IL-2 expression in human T lymphocytes [18].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-26a-mediated regulation of interleukin-2 expression in transformed avian lymphocyte lines

Yao

Smith

et al. 2010

Cancer Cell Int

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BackgroundMicro(mi)RNAs are a class of small non-coding RNAs that play critical roles in the induction of various cancers, including lymphomas induced by oncogenic viruses. While some of the miRNAs are oncogenic, miRNAs such as miR-26a are consistently downregulated in a number of cancers, demonstrating their potential tumor suppressor functions. Global miRNA expression profiles of a number of virus-transformed avian lymphoma cell lines have shown downregulation of gga-miR-26a expression, irrespective of molecular mechanisms of transformation or the viral aetiology. The neoplastic transformation of lymphocytes by many viruses accompanies high levels of proliferative responses, mostly mediated through cytokines such as IL-2. Chicken IL-2 can modulate T-cell proliferation and cytotoxicity in vitro and in vivo and dysregulation of IL-2 expression is observed in diseases such as leukaemia.ResultsThe expression levels of gga-miR-26a in chicken lymphoma cells transformed by 3 distinct avian oncogenic viruses, viz Marek's disease virus (MDV), avian leukosis virus (ALV) and Reticuloendotheliosis virus (REV) were consistently downregulated compared to the levels in the normal lymphocytes. This downregulation of miR-26a regardless of the viral etiology and molecular mechanisms of transformation was consistent with the tumor suppressor role of this miRNA. Notwithstanding this well-established role in cancer, we demonstrate the additional role of this miRNA in directly targeting chicken IL-2 through reporter and biochemical assays. The downregulation of miR-26a can relieve the suppressive effect of this miRNA on IL-2 expression.ConclusionsWe show that miR-26a is globally downregulated in a number of avian lymphoma cells irrespective of the mechanisms of transformation, reiterating the highly conserved tumor suppressor function of this miRNA. However, with the potential for directly targeting chicken IL-2, the downregulation of miR-26a in these tumor cells could relieve the inhibitory effect on IL-2 expression assisting in the proliferative features of the transformed lymphocyte lines.

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Chapter 4 Micromanagers of Immune Cell Fate and Function

Cited by 16 publications

References 97 publications

Antiviral Response Dictated by Choreographed Cascade of Transcription Factors

Antiviral Response Dictated by Choreographed Cascade of Transcription Factors

New nanomedicine approaches using gold–thioguanine nanoconjugates as metallo-ligands

MicroRNA-26a-mediated regulation of interleukin-2 expression in transformed avian lymphocyte lines

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