ORCID Profile
0000-0003-3155-1211
Current Organisations
Vrije Universiteit Brussel
,
University of Zurich
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Publisher: MDPI AG
Date: 28-02-2018
DOI: 10.3390/IJMS19030684
Publisher: Elsevier BV
Date: 12-2009
Publisher: Springer Science and Business Media LLC
Date: 22-10-2022
DOI: 10.1038/S41419-022-05337-Z
Abstract: X-linked lymphoproliferative disease (XLP) is either caused by loss of the SLAM-associated protein (SAP XLP-1) or the X-linked inhibitor of apoptosis (XIAP XLP-2). In both instances, infection with the oncogenic human Epstein Barr virus (EBV) leads to pathology, but EBV-associated lymphomas only emerge in XLP-1 patients. Therefore, we investigated the role of XIAP during B cell transformation by EBV. Using humanized mice, IAP inhibition in EBV-infected mice led to a loss of B cells and a tendency to lower viral titers and lymphomagenesis. Loss of memory B cells was also observed in four newly described patients with XIAP deficiency. EBV was able to transform their B cells into lymphoblastoid cell lines (LCLs) with similar growth characteristics to patient mothers’ LCLs in vitro and in vivo. Gene expression analysis revealed modest elevated lytic EBV gene transcription as well as the expression of the tumor suppressor cell adhesion molecule 1 (CADM1). CADM1 expression on EBV-infected B cells might therefore inhibit EBV-associated lymphomagenesis in patients and result in the absence of EBV-associated malignancies in XLP-2 patients.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2010
DOI: 10.1038/CDD.2009.178
Abstract: On TNF binding, receptor-interacting protein kinase 1 (RIPK1) is recruited to the cytoplasmic domain of TNFR1, at which it becomes ubiquitylated and serves as a platform for recruitment and activation of NEMO/IKK1/IKK2 and TAK1/TAB2. RIPK1 is commonly thought to be required for the activation of canonical NF-kappaB and for inhibition TNFR1-induced apoptosis. RIPK1 has, however, also been reported to be essential for TNFR1-induced apoptosis when cIAPs are depleted. To determine the role of RIPK1 in TNF/IAP antagonist-induced death, we compared wild type (WT) and RIPK1(-/-) mouse embryonic fibroblasts (MEFs) treated with these compounds. On being treated with TNF plus IAP antagonist, RIPK1(-/-) MEFs survived, unlike WT MEFs, demonstrating a killing activity of RIPK1. Surprisingly, however, on being treated with TNF alone, RIPK1(-/-) MEFs activated canonical NF-kappaB and did not die. Furthermore, several cell types from E18 RIPK1(-/-) embryos seem to activate NF-kappaB in response to TNF. These data indicate that models proposing that RIPK1 is essential for TNFR1 to activate canonical NF-kappaB are incorrect.
Publisher: Public Library of Science (PLoS)
Date: 08-01-2010
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2004
DOI: 10.1158/0008-5472.CAN-04-0866
Abstract: The statin family of drugs are well-established inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and are used clinically in the control of hypercholesterolemia. Recent evidence, from ourselves and others, shows that statins can also trigger tumor-specific apoptosis by blocking protein geranylgeranylation. We and others have proposed that statins disrupt localization and function of geranylgeranylated proteins responsible for activating signal transduction pathways essential for the growth and/or survival of transformed cells. To explore this further, we have investigated whether the mitogen-activated protein kinase (MAPK) signaling cascades play a role in regulating statin-induced apoptosis. Cells derived from acute myelogenous leukemia (AML) are used as our model system. We show that p38 and c-Jun NH2-terminal kinase/stress-activated kinase MAPK pathways are not altered during lovastatin-induced apoptosis. By contrast, exposure of primary and established AML cells to statins results in significant disruption of basal extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Addition of geranylgeranyl PPi reverses statin-induced loss of ERK1/2 phosphorylation and apoptosis. By establishing and evaluating the inducible Raf-1:ER system in AML cells, we show that constitutive activation of the Raf/MAPK kinase (MEK)/ERK pathway significantly represses but does not completely block lovastatin-induced apoptosis. Our results strongly suggest statins trigger apoptosis by regulating several signaling pathways, including the Raf/MEK/ERK pathway. Indeed, down-regulation of the Raf/MEK/ERK pathway potentiates statin-induced apoptosis because exposure to the MEK1 inhibitor PD98059 sensitizes AML cells to low, physiologically achievable concentrations of lovastatin. Our study suggests that lovastatin, alone or in combination with a MEK1 inhibitor, may represent a new and immediately available therapeutic approach to combat tumors with activated ERK1/2, such as AML.
Publisher: MDPI AG
Date: 03-02-2021
Abstract: In this study, we determined whether Smac mimetics play a role in metastasis, specifically in circulation, tumor extravasation and growth in a metastatic site. Reports suggest inducing the degradation of IAPs through use of Smac mimetics, alters the ability of the tumor cell to metastasize. However, a role for the immune or stromal compartment in affecting the ability of tumor cells to metastasize upon loss of IAPs has not been defined. To address this open question, we utilized syngeneic tumor models in a late-stage model of metastasis. Loss of cIAP1 in the endothelial compartment, rather than depletion of cIAP2 or absence of cIAP1 in the hematopoietic compartment, caused reduction of tumor load in the lung. Our results underline the involvement of the endothelium in hindering tumor cell extravasation upon loss of cIAP1, in contrast to the immune compartment. Endothelial specific depletion of cIAP1 did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a decrease in tumor cell extravasation. Surprisingly, lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells, was critical for the extravasation. Using TCGA, we found high LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advanced disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, reduce metastasis to the lung by inhibiting tumor cell extravasation.
Publisher: Cold Spring Harbor Laboratory
Date: 14-09-2019
DOI: 10.1101/766485
Abstract: Metastasis involves the interaction of the tumor, immune and endothelial cells. Cell death proteins, such as inhibitors of apoptosis proteins (IAPs), are critical players in survival, inflammation and permeability. Whether the use of Smac mimetics, which target cIAP1/2 for degradation would affect metastasis is unknown. We show Smac mimetics reduced metastasis due to the loss of cIAP1 but not cIAP2 in experimental metastasis models. The endothelial compartment rather than the immune cells was responsible for reduction of extravasation upon loss of cIAP1. Loss of cIAP1 in primary endothelial cells did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a reduction in tumor cell extravasation. Unexpectedly, the co-loss of TNFR1 and cIAP1 restored the tumor load. We were surprised to find lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells was critical for the extravasation. Using TCGA data, we found high levels of LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advance disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, may reduce metastasis to the lung through a LTA/TNFR mechanism by altering the endothelial barrier and inhibiting the ability of tumor cells to extravasate.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.CELL.2015.08.031
Abstract: The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2019
DOI: 10.1038/S41419-019-1938-X
Abstract: The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap −/− macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap −/− myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components.
Publisher: Elsevier BV
Date: 2009
Publisher: American Association for Cancer Research (AACR)
Date: 06-2007
DOI: 10.1158/1535-7163.MCT-06-0745
Abstract: Statins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (P = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM. [Mol Cancer Ther 2007 (6):1886–97]
Publisher: Springer Science and Business Media LLC
Date: 16-03-2012
DOI: 10.1038/CDD.2012.32
Publisher: Elsevier BV
Date: 04-2011
Publisher: American Association for the Advancement of Science (AAAS)
Date: 27-08-2019
DOI: 10.1126/SCISIGNAL.AAW3469
Abstract: By promoting noncanonical NF-κB signaling, SMAC mimetics can reprogram CD4 + T helper cell differentiation and curb autoimmunity.
Publisher: Rockefeller University Press
Date: 07-07-2008
Abstract: Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor κB (NF-κB) signaling, and sensitize cells to tumor necrosis factor α (TNFα). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1–Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1–TRAF2 in a cIAP1-dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless promotes the same noncanonical NF-κB signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNFα-induced death occurs. TWEAK-induced loss of the cIAP1–TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNFα-induced death, whereas primary cells remain resistant. Conversely, cIAP1–TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNFα sensitization. Lysosomal degradation of cIAP1–TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.CCELL.2016.01.006
Abstract: Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.
Publisher: American Society of Hematology
Date: 17-04-2014
DOI: 10.1182/BLOOD-2013-06-510743
Abstract: cIAPs and XIAP negatively regulate cytokine production, including TNF to disrupt myeloid lineage differentiation. IAPs prevent RIPK1 and RIPK3 activity to limit cytokine production prior to cell death.
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S0960-9822(03)00297-5
Abstract: The c-myc proto-oncogene encodes a transcription factor, c-Myc, which is deregulated and/or overexpressed in many human cancers. Despite c-Myc's importance, the identity of Myc-regulated genes and the mechanism by which Myc regulates these genes remain unclear. By combining chromatin immunoprecipitation with CpG island arrays, we identified 177 human genomic loci that are bound by Myc in vivo. Analyzing a cohort of known and novel Myc target genes showed that Myc-associated protein X, Max, also bound to these regulatory regions. Indeed, Max is bound to these loci in the presence or absence of Myc. The Myc:Max interaction is essential for Myc-dependent transcriptional activation however, we show that Max bound targets also include Myc-repressed genes. Moreover, we show that the interaction between Myc and Max is essential for gene repression to occur. Taken together, the identification and analysis of Myc bound target genes supports a model whereby Max plays an essential and universal role in the mechanism of Myc-dependent transcriptional regulation.
Publisher: eLife Sciences Publications, Ltd
Date: 23-12-2015
DOI: 10.7554/ELIFE.10592
Abstract: TRAF2 is a component of TNF superfamily signalling complexes and plays an essential role in the regulation and homeostasis of immune cells. TRAF2 deficient mice die around birth, therefore its role in adult tissues is not well-explored. Furthermore, the role of the TRAF2 RING is controversial. It has been claimed that the atypical TRAF2 RING cannot function as a ubiquitin E3 ligase but counterclaimed that TRAF2 RING requires a co-factor, sphingosine-1-phosphate, that is generated by the enzyme sphingosine kinase 1, to function as an E3 ligase. Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-κB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation. This inflammation was driven by TNF, cell death, non-canonical NF-κB and the adaptive immune system, and might therefore represent a clinically relevant model of psoriasis. TRAF2 therefore has essential tissue specific functions that do not overlap with those of Sphk1.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2010
Abstract: Novel therapeutic agents that selectively induce tumor cell death are urgently needed in the clinical management of cancers. Such agents would constitute effective adjuvant approaches to traditional chemotherapy regimens. Organosulfur compounds (OSCs), such as diallyl disulfide, have demonstrated anti-proliferative effects on cancer cells. We have previously shown that synthesized relatives of dysoxysulfone, a natural OSC derived from the Fijian medicinal plant, Dysoxylum richi , possess tumor-specific antiproliferative effects and are thus promising lead candidates. Because our structure-activity analyses showed that regions flanking the disulfide bond mediated specificity, we synthesized 18 novel OSCs by structural modification of the most promising dysoxysulfone derivatives. These compounds were tested for anti-proliferative and apoptotic activity in both normal and leukemic cells. Six OSCs exhibited tumor-specific killing, having no effect on normal bone marrow, and are thus candidates for future toxicity studies. We then employed mRNA expression profiling to characterize the mechanisms by which different OSCs induce apoptosis. Using Gene Ontology analysis we show that each OSC altered a unique set of pathways, and that these differences could be partially rationalized from a transcription factor binding site analysis. For ex le, five compounds altered genes with a large enrichment of p53 binding sites in their promoter regions (p 0.0001). Taken together, these data establish OSCs derivatized from dysoxysulfone as a novel group of compounds for development as anti-cancer agents.
Publisher: Springer Science and Business Media LLC
Date: 09-2001
Abstract: Lovastatin is an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the major regulatory enzyme of the mevalonate pathway. We have previously reported that lovastatin induces a significant apoptotic response in human acute myeloid leukemia (AML) cells. To identify the critical biochemical mechanism(s) essential for lovastatin-induced apoptosis, add-back experiments were conducted to determine which downstream product(s) of the mevalonate pathway could suppress this apoptotic response. Apoptosis induced by lovastatin was abrogated by mevalonate (MVA) and geranylgeranyl pyrophosphate (GGPP), and was partially inhibited by farnesyl pyrophosphate (FPP). Other products of the mevalonate pathway including cholesterol, squalene, lanosterol, desmosterol, dolichol, dolichol phosphate, ubiquinone, and isopentenyladenine did not affect lovastatin-induced apoptosis in AML cells. Our results suggest that inhibiting geranylgeranylation of target proteins is the predominant mechanism of lovastatin-induced apoptosis in AML cells. In support of this hypothesis, the geranylgeranyl transferase inhibitor (GGTI-298) mimicked the effect of lovastatin, whereas the farnesyl transferase inhibitor (FTI-277) was much less effective at triggering apoptosis in AML cells. Inhibition of geranylgeranylation was monitored and associated with the apoptotic response induced by lovastatin and GGTI-298 in the AML cells. We conclude that blockage of the mevalonate pathway, particularly inhibition of protein geranylgeranylation holds a critical role in the mechanism of lovastatin-induced apoptosis in AML cells.
Publisher: American Society for Clinical Investigation
Date: 22-10-2019
DOI: 10.1172/JCI122767
Publisher: Springer Science and Business Media LLC
Date: 04-2002
Abstract: The objective of this study was to identify biologic parameters that were associated with either exceptionally good or poor outcome in childhood acute myeloid leukemia (AML). Among the children with AML who entered Children's Cancer Group trial 213, 498 patients without Down syndrome or acute promyelocytic leukemia (APL) comprise the basis for this report. Univariate comparisons of the proportion of patients attaining complete remission after induction (CR) indicate that, at diagnosis, male gender, low platelet count ( 15%) bone marrow (BM) blasts on day 14 of the first course of induction, and +8 are associated with lower CR rates, while abnormal 16 is associated with a higher CR rate. Multivariate analysis suggests high platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, 20 000/microl), absence of hepatomegaly, low percentage of BM blasts (< or =15%), and abnormal 16 with overall survival. Absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 were determined to be independent prognostic factors associated with better survival.
Publisher: Springer Science and Business Media LLC
Date: 10-10-2014
DOI: 10.1007/S00125-014-3407-5
Abstract: Type 1 diabetes results from T cell-mediated destruction of pancreatic beta cells. The mechanisms of beta cell destruction in vivo, however, remain unclear. We aimed to test the relative roles of the main cell death pathways: apoptosis, necrosis and necroptosis, in beta cell death in the development of CD4(+) T cell-mediated autoimmune diabetes. We altered expression levels of critical cell death proteins in mouse islets and tested their ability to survive CD4(+) T cell-mediated attack using an in vivo graft model. Loss of the B cell leukaemia/lymphoma 2 (BCL-2) homology domain 3-only proteins BIM, PUMA or BID did not protect beta cells from this death. Overexpression of the anti-apoptotic protein BCL-2 or combined deficiency of the pro-apoptotic multi-BCL2 homology domain proteins BAX and BAK also failed to prevent beta cell destruction. Furthermore, loss of function of the death receptor Fas or its essential downstream signalling molecule Fas-associated death domain (FADD) in islets was also not protective. Using electron microscopy we observed that dying beta cells showed features of necrosis. However, islets deficient in receptor-interacting serine/threonine protein kinase 3 (RIPK3), a critical initiator of necroptosis, were still normally susceptible to CD4(+) T cell-mediated destruction. Remarkably, simultaneous inhibition of apoptosis and necroptosis by combining loss of RIPK3 and overexpression of BCL-2 in islets did not protect them against immune attack either. Collectively, our data indicate that beta cells die by necrosis in autoimmune diabetes and that the programmed cell death pathways apoptosis and necroptosis are both dispensable for this process.
Publisher: eLife Sciences Publications, Ltd
Date: 02-12-2014
DOI: 10.7554/ELIFE.03464
Abstract: SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.
Publisher: Springer Science and Business Media LLC
Date: 09-05-2018
DOI: 10.1038/S41419-018-0508-Y
Abstract: Inhibitor of Apoptosis Proteins act as E3 ubiquitin ligases to regulate NF-κB signalling from multiple pattern recognition receptors including NOD2, as well as TNF Receptor Superfamily members. Loss of XIAP in humans causes X-linked Lymphoproliferative disease type 2 (XLP-2) and is often associated with Crohn’s disease. Crohn’s disease is also caused by mutations in the gene encoding NOD2 but the mechanisms behind Crohn’s disease development in XIAP and NOD2 deficient-patients are still unknown. Numerous other mutations causing Crohn’s Disease occur in genes controlling various aspects of autophagy, suggesting a strong involvement of autophagy in preventing Crohn’s disease. Here we show that the IAP proteins cIAP2 and XIAP are required for efficient fusion of lysosomes with autophagosomes. IAP inhibition or loss of both cIAP2 and XIAP resulted in a strong blockage in autophagic flux and mitophagy, suggesting that XIAP deficiency may also drive Crohn’s Disease due to defects in autophagy.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Springer Science and Business Media LLC
Date: 13-10-2016
Abstract: Neutrophils are essential players in the first-line defense against invading bacteria and fungi. Besides its antiapoptotic role, the inhibitor of apoptosis protein (IAP) family member X-linked IAP (XIAP) has been shown to regulate innate immune signaling. Whereas the role of XIAP in innate signaling pathways is derived mostly from work in macrophages and dendritic cells, it is not known if and how XIAP contributes to these pathways in neutrophils. Here we show that in response to bacterial lipopolysaccharides (LPS), mouse neutrophils secreted considerable amounts of tumor necrosis factor- α (TNF α ) and interleukin-1 β (IL-1 β ) and, in accordance with earlier reports, XIAP prevented LPS-induced hypersecretion of IL-1 β also in neutrophils. Interestingly, and in contrast to macrophages or dendritic cells, Xiap -deficient neutrophils were insensitive to LPS-induced cell death. However, combined loss of function of XIAP and cIAP1/-2 resulted in rapid neutrophil cell death in response to LPS. This cell death occurred by classical apoptosis initiated by a TNF α - and RIPK1-dependent, but RIPK3- and MLKL-independent, pathway. Inhibition of caspases under the same experimental conditions caused a shift to RIPK3-dependent cell death. Accordingly, we demonstrate that treatment of neutrophils with high concentrations of TNF α induced apoptotic cell death, which was fully blockable by pancaspase inhibition in wild-type neutrophils. However, in the absence of XIAP, caspase inhibition resulted in a shift from apoptosis to RIPK3- and MLKL-dependent necroptosis. Loss of XIAP further sensitized granulocyte–macrophage colony-stimulating factor (GM-CSF)-primed neutrophils to TNF α -induced killing. These data suggest that XIAP antagonizes the switch from TNF α -induced apoptosis to necroptosis in mouse neutrophils. Moreover, our data may implicate an important role of neutrophils in the development of hyperinflammation and disease progression of patients diagnosed with X-linked lymphoproliferative syndrome type 2, which are deficient in XIAP.
Publisher: Elsevier BV
Date: 2016
Publisher: Elsevier BV
Date: 08-2017
Publisher: eLife Sciences Publications, Ltd
Date: 27-06-2017
DOI: 10.7554/ELIFE.29849
Publisher: Wiley
Date: 10-02-2012
Publisher: Elsevier BV
Date: 03-2016
Publisher: Springer Science and Business Media LLC
Date: 03-2011
DOI: 10.1038/NATURE09816
Abstract: Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKγ or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin(cpdm/cpdm)) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling.
Publisher: EMBO
Date: 16-08-2021
Publisher: Springer Science and Business Media LLC
Date: 02-02-2017
Abstract: Necroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 1, 3 (RIPK1, RIPK3) and mixed lineage kinase domain-like protein (MLKL). The kinase of RIPK3 phosphorylates MLKL causing MLKL to form a pore-like structure, allowing intracellular contents to release and cell death to occur. Alternatively, RIPK1 and RIPK3 have been shown to regulate cytokine production directly influencing inflammatory immune infiltrates. Recent data suggest that necroptosis may contribute to the malignant transformation of tumor cells in vivo and we asked whether necroptosis may have a role in the tumor microenvironment altering the ability of the tumor to grow or metastasize. To determine if necroptosis in the tumor microenvironment could promote inflammation alone or by initiating necroptosis and thereby influencing growth or metastasis of tumors, we utilized a syngeneic tumor model of metastasis. Loss of RIPK3 in the tumor microenvironment reduced the number of tumor nodules in the lung by 46%. Loss of the kinase activity in RIPK1, a member of the necrosome also reduced tumor nodules in the lung by 38%. However, the loss of kinase activity in RIPK3 or the loss of MLKL only marginally altered the ability of tumor cells to form in the lung. Using bone marrow chimeras, the decrease in tumor nodules in the Ripk3 −/− appeared to be due to the stromal compartment rather than the hematopoietic compartment. Transmigration assays showed decreased ability of tumor cells to transmigrate through the vascular endothelial layer, which correlated with decreased permeability in the Ripk3 −/− mice after tumor injection. In response to permeability factors, such as vascular endothelial growth factor, RIPK3 null endothelial cells showed decreased p38/HSP27 activation. Taken together, our results suggest an alternative function for RIPK1/RIPK3 in vascular permeability leading to decreased number of metastasis.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2006
Abstract: The nuclear factor-kappaB (NF-kappaB) signalling pathway serves a crucial role in regulating the transcriptional responses of physiological processes that include cell ision, cell survival, differentiation, immunity and inflammation. Here we outline studies using mouse models in which the core components of the NF-kappaB pathway, namely the IkappaB kinase subunits (IKKalpha, IKKbeta and NEMO), the IkappaB proteins (IkappaBalpha, IkappaBbeta, IkappaBvarepsilon and Bcl-3) and the five NF-kappaB transcription factors (NF-kappaB1, NF-kappaB2, c-Rel, RelA and RelB), have been genetically manipulated using transgenic and knockout technology.
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.MOLCEL.2012.04.014
Abstract: Nucleotide-binding and oligomerization domain (NOD)-like receptors constitute a first line of defense against invading bacteria. X-linked Inhibitor of Apoptosis (XIAP) is implicated in the control of bacterial infections, and mutations in XIAP are causally linked to immunodeficiency in X-linked lymphoproliferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. We further show that LUBAC activity is required for efficient NF-κB activation and secretion of proinflammatory cytokines after NOD2 stimulation. Remarkably, XLP-2-derived XIAP variants have impaired ubiquitin ligase activity, fail to ubiquitylate RIPK2, and cannot facilitate NOD2 signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis.
Publisher: CSIRO Publishing
Date: 2005
DOI: 10.1071/CH03105
Abstract: Some disulfides have previously been shown to possess antifungal and/or antileukaemic activity. Importantly, this cytotoxicity can be selective. We have previously shown that a subset of these compounds does not block the proliferative potential of normal, non-transformed cells. Based on these results and proposed mechanisms of action, a new set of structurally modified organosulfur compounds, including α-substituted disulfides and a thiosulfonate ester, have been prepared and evaluated for their potential as antileukaemic agents. Compounds were screened for antiproliferative activity against a panel of human cells derived from acute lymphocytic and acute myelogenous leukaemia, as well as non-transformed cells. We have identified five new disulfides and a thiosulfonate that can trigger tumour cells to undergo cell death by an apoptotic mechanism in a sensitive and specific manner.
Publisher: Elsevier BV
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 20-01-2017
DOI: 10.1038/CDD.2016.147
Publisher: Elsevier BV
Date: 04-2017
Publisher: Wiley
Date: 03-01-2017
DOI: 10.1038/ICB.2016.118
Abstract: Understanding how inhibitor of apoptosis proteins (IAPs) regulate apoptosis and necroptosis has been fast-forwarded by the use of Smac mimetics (SMs) to deplete or inhibit the IAPs, specifically cIAP1, cIAP2 and XIAP. The loss or inhibition of cIAP1, cIAP2 and XIAP causes the majority of cells to be sensitized to death receptor induced cell death, such as with tumour necrosis factor (TNF). Mouse genetics shows that there is some functional redundancy and the use of SMs has allowed us to understand how changing the composition of proteins recruited to TNF receptor 1 on TNF ligation can alter protein complex formation and activation of apoptosis or necroptosis, particularly when caspases are inhibited. Determining when or how caspase inhibition occurs physiologically combined with the loss of IAPs will be the next challenge in understanding the ability of IAPs to prevent cell death and/or limit inflammation.
Publisher: Elsevier BV
Date: 02-2012
Publisher: Oxford University Press (OUP)
Date: 30-09-2009
DOI: 10.1093/JMCB/MJP019
Abstract: Ubiquitylation of caspase-8 by the Cullin3 E3 ligase allows its translocation to cytosolic aggregates in the cell by p62/sequestosome-1, increasing caspase-8 activation and thus leading to TRAIL-induced cell death.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.CELL.2007.10.037
Abstract: XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer.
Publisher: Rockefeller University Press
Date: 28-12-2009
Abstract: A role for cellular inhibitors of apoptosis (IAPs [cIAPs]) in preventing CD95 death has been suspected but not previously explained mechanistically. In this study, we find that the loss of cIAPs leads to a dramatic sensitization to CD95 ligand (CD95L) killing. Surprisingly, this form of cell death can only be blocked by a combination of RIP1 (receptor-interacting protein 1) kinase and caspase inhibitors. Consistently, we detect a large increase in RIP1 levels in the CD95 death-inducing signaling complex (DISC) and in a secondary cytoplasmic complex (complex II) in the presence of IAP antagonists and loss of RIP1-protected cells from CD95L/IAP antagonist–induced death. Cells resistant to CD95L/IAP antagonist treatment could be sensitized by short hairpin RNA–mediated knockdown of cellular FLICE-inhibitory protein (cFLIP). However, only cFLIPL and not cFLIPS interfered with RIP1 recruitment to the DISC and complex II and protected cells from death. These results demonstrate a fundamental role for RIP1 in CD95 signaling and provide support for a physiological role of caspase-independent death receptor–mediated cell death.
Publisher: Wiley
Date: 18-04-2008
DOI: 10.1002/IUB.51
Abstract: Bcl-2 family members are the arbiters of mitochondrial apoptotic pathway, which is conserved through evolution. The stoichiometry of pro- versus antiapoptotic Bcl-2 family members in the cell determines whether the cell lives or dies. This fine balance is regulated at the transcriptional or posttranslational level in response to various cellular cues. These signals are transmitted through the upstream molecules in the pathway, that is, the BH3-only molecules that results in the activation of the adaptor molecules, Bax and Bak, at the mitochondrial surface ensuing mitochondrial dysfunction and apoptosis. Understanding the activation process offers a great potential in the therapeutic intervention of many diseases such as cancer and autoimmune disorders.
Publisher: Wiley
Date: 02-12-2015
Publisher: Springer Science and Business Media LLC
Date: 23-01-2020
DOI: 10.1038/S41419-020-2261-2
Abstract: The original version of this article contained an error in the name of one of the co-authors (Erika Owsley). This has been corrected in the PDF and HTML versions.
Publisher: Springer Science and Business Media LLC
Date: 04-2002
Abstract: The statin family of drugs target HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.
Publisher: Wiley
Date: 20-05-2022
DOI: 10.1002/PBC.29783
Abstract: Pain in children living with and beyond cancer is understudied and undertreated. Pain science education (PSE) is a conceptual change strategy facilitating patients’ understanding of the biopsychosocial aspects of pain. Preliminary studies on the adaptation of PSE interventions to adults with and beyond cancer provide a foundation for pediatric research. PSE could help childhood cancer survivors experiencing persistent pain and pain‐related worry after active treatment. PSE may also help children receiving cancer treatment, providing them with a foundation of adaptive pain beliefs and cognitions, and preparing them for procedural and treatment‐related pain. We direct this paper toward pediatric oncology clinicians, policy makers, and researchers working with children living with and beyond cancer. We aim to (a) identify challenges in adapting PSE for children living with and beyond cancer, (b) offer possible solutions, and (c) propose research questions to guide the implementation of PSE for children living with and beyond cancer.
Location: Australia
No related grants have been discovered for W. Wei-Lynn Wong.