The Human Herpes Virus 8-encoded Viral FLICE Inhibitory Protein Physically Associates with and Persistently Activates the IκB Kinase Complex

Liu, Li; Eby, Michael T.; Rathore, Nisha; Sinha, Suwan K.; Kumar, Arvind; Chaudhary, Preet M.

doi:10.1074/jbc.m110480200

Cited by 225 publications

(261 citation statements)

References 64 publications

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“…Dissociation of c-FLIP expression from NF-kB activation has also been supported by recent studies. 39,40 NFkB activation is not reduced in c-FLIP-deficient cells. 39 c-FLIP is unable to activate IkB kinase complex in primary effusion lymphoma.…”

Section: Discussionmentioning

confidence: 92%

c-FLICE inhibitory protein expression inhibits T-cell activation

Lai

2003

Cell Death Differ

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Cellular FLICE-inhibitory protein (c-FLIP) inhibits death receptor-mediated apoptosis by specific interaction with FADD and procaspase-8, and may thus interfere with activation events mediated by FADD and caspase-8. Recent studies, however, suggest that c-FLIP also transmits activation signals. The role of c-FLIP on T-cell activation was examined here using several transgenic mice with variable c-FLIP expression. In all c-FLIP-transgenic mice, Fasmediated apoptosis and in vitro activation-induced T-cell death were suppressed, and T-cell proliferation and IL-2 production were inhibited. c-FLIP transgene also promoted in vivo thymocyte death. Higher c-FLIP transgene expression was correlated with a more profound suppression of T-cell activation and a prominent disturbance in mature thymocyte development. There was no evidence of increased activation and proliferation in all c-FLIP-transgenic T cells examined. Instead, suppression of T-cell activation in c-FLIP-transgenic T cells could be a combinatory effect of FADD/caspase-8-dependent signals and c-FLIP-specific activities.

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Section: Discussionmentioning

confidence: 92%

c-FLICE inhibitory protein expression inhibits T-cell activation

Lai

2003

Cell Death Differ

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“…K13 protein was originally believed to protect virally infected cells from death receptor-induced apoptosis by blocking the recruitment and/or activation of caspase 8/FLICE and, as such, is commonly referred to as viral FLICE inhibitory proteins (vFLIP) (Bertin et al, 1997;Hu et al, 1997;Thome et al, 1997). We subsequently showed that K13 protein also possesses the ability to activate the NF-kB pathway (Chaudhary et al, 1999b;Liu et al, 2002). As K13 is one of the few HHV-8-encoded proteins to be expressed in latently infected KS spindle cells (Sarid et al, 1998;Sturzl et al, 1999), in this report we have investigated its role in the upregulation of IL-8 expression and secretion and the signaling pathways involved in this process.…”

Section: Introductionmentioning

confidence: 99%

Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-κB activation

Sun

Matta

et al. 2006

Oncogene

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“…K13 protein was originally believed to protect virally infected cells from death receptor-induced apoptosis by preventing the activation of caspase-8 and, as such, was classified as a viral Fas-associated death domain protein-like IL-1b-converting enzyme inhibitory protein (vFLIP) (Bertin et al, 1997;Hu et al, 1997;Thome et al, 1997). However, we have subsequently shown that K13 is a strong inducer of the NF-kB pathway through the activation of the IkB kinase complex and does not function as a caspase-8 inhibitor (Chaudhary et al, 1999;Liu et al, 2002;Matta et al, 2003;Matta and Chaudhary, 2004;Chugh et al, 2005). We and others have further shown that K13 utilizes the NF-kB pathway to promote cellular transformation, cytokine secretion and protection against growth-factor withdrawal-induced apoptosis Sun et al, 2003aSun et al, , b, 2006.…”

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confidence: 99%

“…(b) 4-OHT induces a dosedependent increase in NF-kB luciferase activity in K13-ER TAMexpressing K562 NF-kB-Luc cells. Cells were treated with the indicated doses of 4-OHT for 12 h before lysis and luciferase activity was measured as described previously (Liu et al, 2002). …”

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confidence: 99%