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doi:10.1038/sj/leu/2402090

Cited by 23 publications

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“…BAD is a BH3-only proapoptotic protein that is tightly regulated by survival factors, and phosphorylation of BAD inhibits its apoptotic function (56,57). BAD can be phosphorylated by Akt We found that knockdown of Bim enhanced survival of VZVinfected cells, delayed plaque formation, and resulted in higher levels of virus replication.…”

Section: Discussionmentioning

confidence: 85%

Inhibition of Bim Enhances Replication of Varicella-Zoster Virus and Delays Plaque Formation in Virus-Infected Cells

Liu

Cohen

2014

J Virol

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Programmed cell death (apoptosis) is an important host defense mechanism against intracellular pathogens, such as viruses. Accordingly, viruses have evolved multiple mechanisms to modulate apoptosis to enhance replication. Varicella-zoster virus (VZV) induces apoptosis in human fibroblasts and melanoma cells. We found that VZV triggered the phosphorylation of the proapoptotic proteins Bim and BAD but had little or no effect on other Bcl-2 family members. Since phosphorylation of Bim and BAD reduces their proapoptotic activity, this may prevent or delay apoptosis in VZV A poptosis is an important host defense mechanism against intracellular pathogens, such as viruses (1-3). Accordingly, viruses have evolved ways to manipulate this pathway to allow efficient virus replication and production of progeny (4). Apoptosis can be triggered by extracellular stimuli, such as tumor necrosis factor alpha (TNF-␣), Fas ligand, or nutrient depletion, which is termed extrinsic apoptosis, or by intracellular stresses, such as endoplasmic reticulum (ER) stress, hypoxia, or DNA damage, which is termed intrinsic apoptosis. The intrinsic apoptosis or mitochondrial pathway is controlled by the interplay between several Bcl-2 family proteins: the prosurvival proteins Bcl-2 (B-cell lymphoma 2), Bcl-xL (Bcl-2 extra large), and Mcl-1 (myeloid cell leukemia 1), as well as the proapoptotic proteins Bax (Bcl-2-associated X protein), Bak (Bcl-2 homologous antagonist/killer), Bim (Bcl-2-interacting mediator of cell death), PUMA (p53-upregulated modulator of apoptosis), NOXA (NADPH oxidase activator 1), Bid (BH3-interacting domain death agonist), and BAD (Bcl-2-associated death promoter). Bax and Bak are effectors of apoptosis that form pores on mitochondrial membranes, resulting in release of cytochrome C and triggering apoptosis (5).Apoptosis is a complex process, and many cellular components and signaling pathways are involved to ensure that it is properly controlled (6). Viruses regulate apoptosis using different mechanisms; most viruses encode proteins to suppress apoptosis, while some RNA viruses trigger apoptosis for virus spread (4). Alphaherpesviruses trigger different apoptosis responses depending on the cell types they infect (7,8). Herpes simplex virus 1 (HSV-1) and HSV-2 encode a number of proteins that inhibit apoptosis (9, 10), including protein kinase US3 (11, 12), glycoprotein J (gJ) (13), and latency-associated transcript (LAT) (14). In addition, HSV mutants deleted for ICP4, ICP27, UL39, and gD undergo apoptosis in a cell-type-specific manner (15-19).Varicella-zoster virus (VZV) is a ubiquitous human alphaherpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) when the virus reactivates. VZV rapidly induces apoptosis (24 to 48 h after infection) in primary human foreskin fibroblasts (HFF) (20) and slowly induces apoptosis in melanoma cells (64 to 72 h after infection, (21) and in Vero cells (72 to 96 h after infection, (22)). VZV also induces apoptosis in B and T cells (23) but not in neu...

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Section: Discussionmentioning

confidence: 85%

Inhibition of Bim Enhances Replication of Varicella-Zoster Virus and Delays Plaque Formation in Virus-Infected Cells

Liu

Cohen

2014

J Virol

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The role of the mitochondria in mediating cytotoxicity of anti-cancer therapies

Nguyen

Hussain

2007

J Bioenerg Biomembr

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Optimal cytotoxic anticancer therapy, at the cellular level, requires effective and selective induction of cell death to achieve a net reduction of biomass of malignant tissues. Standard cytotoxic chemotherapeutics have been developed based on the observations that mitotically active cancer cells are more susceptible than quiescent normal cells to chromosomal, microtubular or metabolic poisons. More recent development of molecularly targeted drugs for cancer focuses on exploiting biological differentials between normal and transformed cells for selective eradication of cancers. The common thread of "standard" and "novel" cytotoxic drugs is their ability to activate the apoptosis-inducing machinery mediated by mitochondria, also known as the intrinsic death signaling cascade. The aim of this article is to provide an overview of the role of the mitochondria, an energy-generating organelle essential for life, in mediating death when properly activated by cytotoxic stresses.

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NFAT5 induction by the pre–T-cell receptor serves as a selective survival signal in T-lymphocyte development

Berga-Bolaños

Alberdi

Buxadé

et al. 2013

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

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The Rel-like transcription factors nuclear factor kappa B (NF-κB) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKKβ regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor αβ thymocytes and the transition from the β-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre-T-cell receptor but exhibited a partial defect in β-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKKβ/NF-κB pathway in thymocytes and as a downstream effector of the prosurvival role of the pre-T-cell receptor.T-cell development | gene expression E arly thymocyte differentiation proceeds through doublenegative (DN; CD4 − and CD8 − ) steps (1, 2) from the DN1 to the early DN3 (E-DN3) stages until cells express a recombined β allele of the T-cell receptor (TCR), which, together with the nonvariant pre-Tα and the CD3 complex, constitute a functional pre-TCR (3). The pre-TCR marks the commitment to the αβ T-cell lineage and controls the β-selection checkpoint in a ligandindependent manner by regulating allelic exclusion of the TCRβ locus, proliferation, survival, and differentiation of thymocytes, all of which are required for progression of DN3 to double-positive (DP; CD4 + and CD8 + ) cells (4-6). At the DP stage, thymocytes recombine the TCRα and express the mature TCRαβ complex, which interacts with self-peptide-MHC complexes of thymic antigen-presenting cells (7). This interaction determines the positive and negative selection of DP thymocytes from which CD4 + or CD8 + single-positive (SP) cells emerge. SP cells then migrate to peripheral organs to populate them with mature T lymphocytes.Despite knowledge accumulated on signaling pathways activated by the pre-TCR, less is known about the specialization of transcription factors downstream from this receptor and the genes they control (8). The Rel-like transcription factors NF-κB and the calcineurin-dependent NFATc proteins regulate thymocyte development downstream of the pre-TCR (9-16). Thymocytes also express the calcineurin-independent NFAT protein NFAT5, which has hybrid features of both NF-κB and NFATc proteins (17,18). NFAT5 protects cells from osmotic stress (19), and NFAT5-deficient mice present severe atrophy of the renal medulla, systemic hypernatremia, and a reduced thymocyte compartment and mature T-cell lymphopenia (20,21). Whereas the thymocyte and T-lymphocyte deficiency of NFAT5-null mice can be explained by their systemic hypernatremia (21, 22), mice expressing a T-lymphocyte-restricted dominant negat...

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Cited by 23 publications

References 53 publications

Inhibition of Bim Enhances Replication of Varicella-Zoster Virus and Delays Plaque Formation in Virus-Infected Cells

Inhibition of Bim Enhances Replication of Varicella-Zoster Virus and Delays Plaque Formation in Virus-Infected Cells

The role of the mitochondria in mediating cytotoxicity of anti-cancer therapies

NFAT5 induction by the pre–T-cell receptor serves as a selective survival signal in T-lymphocyte development

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