Phorbol 12-Myristate 13-Acetate Protects against Tumor Necrosis Factor (TNF)-Induced Necrotic Cell Death by Modulating the Recruitment of TNF Receptor 1-Associated Death Domain and Receptor-Interacting Protein into the TNF Receptor 1 Signaling Complex: Implication for the Regulatory Role of Protein Kinase C

2006 ◽  
Vol 70 (3) ◽  
pp. 1099-1108 ◽  
Author(s):  
Hee Sun Byun ◽  
Kyeong Ah Park ◽  
Minho Won ◽  
Keum-Jin Yang ◽  
Sanghee Shin ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Necrotic Cell Death ◽  
Tnf Receptor ◽  
Death Domain ◽  
Necrotic Cell ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Kinase C ◽  
Necrosis Factor

scholarly journals UXT-V1 protects cells against TNF-induced apoptosis through modulating complex II formation

2011 ◽  
Vol 22 (8) ◽  
pp. 1389-1397 ◽  
Author(s):  
Yuefeng Huang ◽  
Liang Chen ◽  
Yi Zhou ◽  
Heng Liu ◽  
Jueqing Yang ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Receptor Complex ◽  
Tnf Receptor ◽  
Death Domain ◽  
Complex Ii ◽  
Signaling Complex ◽  
Induced Apoptosis ◽  
Necrosis Factor

Proteins that directly regulate tumor necrosis factor (TNF) signaling have critical roles in determining cell death and survival. Previously we characterized ubiquitously expressed transcript (UXT)-V2 as a novel transcriptional cofactor to regulate nuclear factor-κB in the nucleus. Here we report that another splicing isoform of UXT, UXT-V1, localizes in cytoplasm and regulates TNF-induced apoptosis. UXT-V1 knockdown cells are hypersensitive to TNF-induced apoptosis. We demonstrated that UXT-V1 is a new component of TNF receptor signaling complex. We found that UXT-V1 binds to TNF receptor-associated factor 2 and prevents TNF receptor–associated death domain protein from recruiting Fas-associated protein with death domain. More importantly, UXT-V1 is a short-half-life protein, the degradation of which facilitates the formation of the apoptotic receptor complex II in response to TNF treatment. This study demonstrates that UXT-V1 is a novel regulator of TNF-induced apoptosis and sheds new light on the underlying molecular mechanism of this process.

Selective regulation by δ-PKC and PI 3-kinase in the assembly of the antiapoptotic TNFR-1 signaling complex in neutrophils

2004 ◽  
Vol 287 (3) ◽  
pp. C633-C642 ◽  
Author(s):  
Laurie E. Kilpatrick ◽  
Shuang Sun ◽  
Helen M. Korchak
Keyword(s):  
Kinase Activity ◽  
Serine Phosphorylation ◽  
Integrin Signaling ◽  
Tnf Receptor ◽  
Death Domain ◽  
Negative Regulators ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Positive Regulators

TNF is implicated in the attenuation of neutrophil constitutive apoptosis during sepsis. Antiapoptotic signaling is mediated principally through the TNF receptor-1 (TNFR-1). In adherent neutrophils, when β-integrin signaling is activated, TNF phosphorylates TNFR-1 and activates prosurvival and antiapoptotic signaling. Previously, we identified the δ-PKC isotype and phosphatidylinositol (PI) 3-kinase as critical regulators of TNF signaling in adherent neutrophils. Both kinases associate with TNFR-1 in response to TNF and are required for TNFR-1 serine phosphorylation, NF-κB activation, and inhibition of apoptosis. The purpose of this study was to examine the role of δ-PKC and PI 3-kinase in the assembly of TNFR-1 signaling complex that regulates NF-κB activation and antiapoptotic signaling. Coimmunoprecipitation studies established that PI 3-kinase, δ-PKC, and TNFR-1 formed a signal complex in response to TNF. δ-PKC recruitment required both δ-PKC and PI 3-kinase activity, whereas PI 3-kinase recruitment was δ-PKC independent, suggesting that PI 3-kinase acts upstream of δ-PKC. An important regulatory step in control of antiapoptotic signaling is the assembly of the TNFR-1-TNFR-1-associated death domain protein (TRADD)-TNFR-associated factor 2 (TRAF2)-receptor interacting protein (RIP) complex that controls NF-κB activation. Inhibition of either δ-PKC or PI 3-kinase decreased TNF-mediated recruitment of RIP and TRAF2 to TNFR-1. In contrast, TRADD recruitment was enhanced. Thus δ-PKC and PI 3-kinase are positive regulators of TNF-mediated association of TRAF2 and RIP with TNFR-1. Conversely, these kinases are negative regulators of TRADD association. These results suggest that δ-PKC and PI 3-kinase regulate TNF antiapoptotic signaling at the level of the TNFR-1 through control of assembly of a TNFR-1-TRADD-RIP-TRAF2 complex.

scholarly journals A Regulatory Role for TRAF1 in Antigen-induced Apoptosis of  T Cells

1997 ◽  
Vol 185 (10) ◽  
pp. 1777-1783 ◽  
Author(s):  
Daniel E. Speiser ◽  
Soo Young Lee ◽  
Brian Wong ◽  
Joseph Arron ◽  
Angela Santana ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Cytokine Production ◽  
Biological Effects ◽  
Tumor Necrosis Factor Receptor ◽  
Tnf Receptor ◽  
Cell Type ◽  
Signaling Complex ◽  
Induced Apoptosis ◽  
Necrosis Factor

Tumor necrosis factor receptor (TNFR)–associated factor 2 (TRAF2) and TRAF1 were found as components of the TNFR2 signaling complex, which exerts multiple biological effects on cells such as cell proliferation, cytokine production, and cell death. In the TNFR2-mediated signaling pathways, TRAF2 works as a mediator for activation signals such as NF-κB, but the role of TRAF1 has not been previously determined. Here we show in transgenic mice that TRAF1 overexpression inhibits antigen-induced apoptosis of CD8+ T lymphocytes. Our results demonstrate a biological role for TRAF1 as a regulator of apoptotic signals and also support the hypothesis that the combination of TRAF proteins in a given cell type determines distinct biological effects triggered by members of the TNF receptor superfamily.

scholarly journals The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

2001 ◽  
Vol 21 (12) ◽  
pp. 3986-3994 ◽  
Author(s):  
Anne Devin ◽  
Yong Lin ◽  
Shoji Yamaoka ◽  
Zhiwei Li ◽  
Michael Karin ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Ring Finger ◽  
Tnf Receptor ◽  
Death Domain ◽  
Iκb Kinase ◽  
Cytokine Tumor Necrosis Factor ◽  
Necrosis Factor

ABSTRACT The activation of IκB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-κB. IKK is a complex composed of three subunits: IKKα, IKKβ, and IKKγ (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKα and IKKβ catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKα, IKKβ, and the RING finger domain of TRAF2, and either IKKα or IKKβ alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKγ is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKγ-deficient cells. Using TRAF2−/− cells, we demonstrated that the TNF-induced interaction between IKKγ and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

scholarly journals Inhibition of Tumor Necrosis Factor (TNF) Signal Transduction by the Adenovirus Group C RID Complex Involves Downregulation of Surface Levels of TNF Receptor 1

2004 ◽  
Vol 78 (23) ◽  
pp. 13113-13121 ◽  
Author(s):  
Shawn P. Fessler ◽  
Y. Rebecca Chin ◽  
Marshall S. Horwitz
Keyword(s):  
Plasma Membrane ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tnf Receptor ◽  
Signaling Complex ◽  
Antiviral Responses ◽  
Mechanism Of Inhibition ◽  
Early Transcription ◽  
Necrosis Factor ◽  
Inhibit Tumor Necrosis Factor

ABSTRACT Adenoviruses employ multiple genes to inhibit the host antiviral responses. There is increasing evidence that these immunoregulatory genes may function either during lytic or latent infection. Adenovirus early transcription region 3 (E3) encodes at least seven proteins, five of which block the acquired or innate immune response. Previous findings from this laboratory demonstrated that the E3 proteins 10.4K and 14.5K, which form a complex in the plasma membrane, inhibit tumor necrosis factor (TNF)-induced activation of NF-κB and the synthesis of chemokines. To determine the mechanism of inhibition of these pathways by the adenovirus E3 10.4K/14.5K proteins, we have examined the effects of this viral complex on the inhibition of AP-1 and NF-κB activation by TNF and found a reduction in assembly of the TNF receptor 1 (TNFR1) signaling complex at the plasma membrane accompanied by downregulation of surface levels of TNFR1.

scholarly journals Downregulation of tumor necrosis factor (TNF) sensitivity via modulation of TNF binding capacity by protein kinase C activators.

1987 ◽  
Vol 166 (6) ◽  
pp. 1788-1797 ◽  
Author(s):  
R Unglaub ◽  
B Maxeiner ◽  
B Thoma ◽  
K Pfizenmaier ◽  
P Scheurich
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Binding Capacity ◽  
Receptor Protein ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Kinase C ◽  
Necrosis Factor

The regulatory action of activators for protein kinase C on the specific binding capacity for recombinant human tumor necrosis factor alpha (TNF-alpha) was studied on various human cell lines. Phorbol myristate acetate (PMA) and oleyl acetyl glycerol (OAG) both are able to rapidly downregulate TNF-binding capacity of normal and malignant cells derived from various tissues. As PMA treatment did not enhance internalization of TNF-alpha-receptor complexes at 37 degrees C, and since OAG was able to downregulate TNF-binding capacity under conditions where internalization and shedding of receptor protein are prevented, we conclude that protein kinase C controls ligand affinity of the TNF-receptor protein, possibly via direct phosphorylation. Protein kinase C triggered downregulation of TNF-alpha-binding capacity concomitantly resulted in reduction of TNF-alpha sensitivity, as revealed from decreased cytotoxic action of TNF-alpha on L 929 cells and from inhibition of TNF-alpha-mediated enhancement of HLA class II antigen expression in Colo 205 cells. Restoration of TNF-binding capacity upon abrogation of protein kinase C stimulation leads to full recovery of TNF responsiveness, further supporting the close linkage of TNF-receptor expression and TNF sensitivity. These data suggest that regulation of TNF-binding capacity by protein kinase C is one of the cellular control mechanisms of TNF responsiveness.

scholarly journals Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xuening Wang ◽  
Dan Cheng ◽  
Guanglei Hu ◽  
Lili Liang ◽  
Fei Tan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Receptor Expression ◽  
Structural Basis ◽  
Tnf Receptor ◽  
Death Domain ◽  
Independent Manner ◽  
Normal Keratinocytes ◽  
Apoptosis Protein ◽  
Necrosis Factor

The interaction between tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) regulates the fate of keratinocytes, depending on the relative expression of TNF receptor (TNFR) 1 or TNFR2. However, the precise mechanism underlying this TWEAK-mediated regulation remains unclear. The aim of this study was to provide comprehensive insight into the roles of Fn14, TNFR1/2, and other relevant molecules in the fate of keratinocytes. Further, we sought to elucidate the structural basis for the interaction of TWEAK and Fn14 in regulating cellular outcomes. Normal keratinocytes (mainly expressing TNFR1) and TNFR2-overexpressing keratinocytes were stimulated with TWEAK. Through immunoprecipitation and Western blotting of keratinocyte lysates, we elucidated the associations between Fn14, TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 (cIAP1), and TNFR1/2 molecules. Additionally, we found that TRAF2 exhibited binding to Fn14, cIAP1, and TNFR1/2. Our data suggest that TWEAK induces apoptosis in normal keratinocytes and proliferation in TNFR2-overexpressing keratinocytes in a TNF-α-independent manner; however, inhibition of TRAF2 appears to reverse this effect. Interestingly, the interaction between TWEAK and Fn14 increased TNFR1-associated death domain protein and caspase-8 expression in normal keratinocytes and promoted cytoplasmic import of cIAP1 in TNFR2-overexpressing keratinocytes. In conclusion, we found that the Fn14-TRAF2-TNFR signaling axis mediates TWEAK’s regulation of the fate of keratinocytes, possibly in a manner involving the TNF-α-independent TNFR signal transduction.

scholarly journals The Role of RIPK1 and RIPK3 in Cardiovascular Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8174
Author(s):  
Elise DeRoo ◽  
Ting Zhou ◽  
Bo Liu
Keyword(s):  
Cardiovascular Disease ◽  
Protein Kinase ◽  
Current Evidence ◽  
Venous Disease ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Interacting Protein ◽  
Prevention And Treatment ◽  
Peripheral Arterial

Cardiovascular diseases, including peripheral arterial and venous disease, myocardial infarction, and stroke, are the number one cause of death worldwide annually. In the last 20 years, the role of necroptosis, a newly identified form of regulated necrotic cell death, in cardiovascular disease has come to light. Specifically, the damaging role of two kinase proteins pivotal in the necroptosis pathway, Receptor Interacting Protein Kinase 1 (RIPK1) and Receptor Interacting Protein Kinase 3 (RIPK3), in cardiovascular disease has become a subject of great interest and importance. In this review, we provide an overview of the current evidence supporting a pathologic role of RIPK1 and RIPK3 in cardiovascular disease. Moreover, we highlight the evidence behind the efficacy of targeted RIPK1 and RIPK3 inhibitors in the prevention and treatment of cardiovascular disease.

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