Yu, P.W. et al. Identification of RIP3, a RIP-like kinase that activates apoptosis and NF-B. Curr. Biol. 9, 539-542

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Current Biology (Impact Factor: 9.57). 06/1999; 9(10):539-42. DOI: 10.1016/S0960-9822(99)80239-5
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The tumor necrosis factor receptor 1 (TNFR1) and the Fas receptor recruit complexes formed by the interactions between RIP kinase, TRADD, FADD and RAIDD - adaptor proteins that contain death domains - which in turn recruit other proteins to initiate signaling [1][2][3][4][5]. To identify proteins associated with the TNF signaling pathway, we performed a yeast two-hybrid interaction screen using RIP as bait. We isolated a kinase, RIP3, which shares homology with the kinase domain of RIP and RIP2 (also known as Rick or CARDIAK). RIP3 could be co-immunoprecipitated with RIP, TRAF2 and TNFR1 in mammalian cells. The carboxy-terminal domain of RIP3, like that of RIP, could activate the transcription factor NFkappaB and induce apoptosis when expressed in mammalian cells. Interestingly, this region shares no significant sequence homology to the death domain of RIP, the caspase-recruiting domain (CARD) of RIP2 [6][7][8] or any other apoptosis-inducing domain. As with RIP and RIP2, the kinase domain of RIP3 was not required for either NFkappaB activation or apoptosis induction. Overexpression of a dominant-negative mutant of RIP3 strongly inhibited the caspase activation but not the NFkappaB activation induced by TNFalpha. Therefore, RIP3 appears to function as an intermediary in TNFalpha-induced apoptosis.

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Available from: Donald G Payan, Mar 14, 2014
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    • "Other kinase-dead mutants K51A, D161G, and D143N only drive this oligomerization when high concentrations of RIP3i compound are present. WT RIP3 has a propensity to drive this same process when overexpressed (Kasof et al., 2000; Pazdernik et al., 1999; Sun et al., 1999; Yu et al., 1999). "
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    • "Furthermore, the influence of RIP3 on NF-κB, an inhibitor of apoptosis22,23,24, is controversial. In some studies, NF-κB appears to be induced by RIP3 overexpression25,26, but in other studies, RIP3 has no effect on its activation, but rather, acts by attenuating RIP1 and TNFR1-mediated NF-κB activation27. In any case, PTL could inhibit NF-κB indirectly by blocking IKK-β at cys179 and directly by inhibiting p65 at the cysteine residue in its activation loop, which would contribute to its apoptosis-inducing ability28. "
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    ABSTRACT: Aim: Receptor-interacting protein 3 (RIP3) is involved in tumor necrosis factor receptor signaling, and results in NF-κB-mediated prosurvival signaling and programmed cell death. The aim of this study was to determine whether overexpression of the RIP3 gene could sensitize human breast cancer cells to parthenolide in vitro. Methods: The expression of RIP3 mRNA in human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435 and T47D) was detected using RT-PCR. Both MDA-MB-231 and MCF-7 cells were transfected with RIP3 expression or blank vectors via lentivirus. Cell viability was measured with MTT assay; intracellular ROS level and cell apoptosis were analyzed using flow cytometry. Results: RIP3 mRNA expression was not detected in the four human breast cancer cell lines tested. However, the transfection induced higher levels of RIP3 protein in MCF-7 and MDA-MB-231 cells. Furthermore, overexpression of RIP3 decreased the IC50 values of parthenolide from 17.6 to 12.6 μmol/L in MCF-7 cells, and from 16.6 to 9.9 μmol/L in MDA-MB-231 cells. Moreover, overexpression of RIP3 significantly increased parthenolide-induced apoptosis and ROS accumulation in MCF-7 and MDA-MB-231 cells. Pretreatment with N-acetyl-cysteine abrogated the increased sensitivity of RIP3-transfected MCF-7 and MDA-MB-231 cells to parthenolide. Conclusion: Overexpression of RIP3 sensitizes MCF-7 and MDA-MB-231 breast cancer cells to parthenolide in vitro via intracellular ROS accumulation.
    Acta Pharmacologica Sinica 06/2014; 35(7). DOI:10.1038/aps.2014.31 · 2.91 Impact Factor
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    • "Early experiments using overexpression systems implicate RIP3 in apoptosis and NF-kB signaling (Sun et al. 1999; Yu et al. 1999; Meylan et al. 2004). However, RIP3 À/À thymocytes responded normally to different apoptosis stimuli, and RIP3 À/À fibroblasts or macrophages were normal for TNF-and toll-like receptor (TLR) ligand-induced NF-kB activation (Newton et al. 2004). "
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    ABSTRACT: The receptor-interacting protein kinase 3 (RIP3/RIPK3) has emerged as a critical regulator of programmed necrosis/necroptosis, an inflammatory form of cell death with important functions in pathogen-induced and sterile inflammation. RIP3 activation is tightly regulated by phosphorylation, ubiquitination, and caspase-mediated cleavage. These post-translational modifications coordinately regulate the assembly of a macromolecular signaling complex termed the necrosome. Recently, several reports indicate that RIP3 can promote inflammation independent of its pronecrotic activity. Here, we review our current understanding of the mechanisms that drive RIP3-dependent necrosis and its role in different inflammatory diseases.
    Genes & development 08/2013; 27(15):1640-9. DOI:10.1101/gad.223321.113 · 10.80 Impact Factor
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