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Siegmund D, Wagner J, Wajant H. TNF Receptor Associated Factor 2 (TRAF2) Signaling in Cancer. Cancers (Basel) 2022; 14:cancers14164055. [PMID: 36011046 PMCID: PMC9406534 DOI: 10.3390/cancers14164055] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/05/2022] [Accepted: 08/19/2022] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) is an intracellular adapter protein with E3 ligase activity, which interacts with a plethora of other signaling proteins, including plasma membrane receptors, kinases, phosphatases, other E3 ligases, and deubiquitinases. TRAF2 is involved in various cancer-relevant cellular processes, such as the activation of transcription factors of the NFκB family, stimulation of mitogen-activated protein (MAP) kinase cascades, endoplasmic reticulum (ER) stress signaling, autophagy, and the control of cell death programs. In a context-dependent manner, TRAF2 promotes tumor development but it can also act as a tumor suppressor. Based on a general description, how TRAF2 in concert with TRAF2-interacting proteins and other TRAF proteins act at the molecular level is discussed for its importance for tumor development and its potential usefulness as a therapeutic target in cancer therapy. Abstract Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.
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Rho SB, Byun HJ, Kim BR, Lee CH. Snail Promotes Cancer Cell Proliferation via Its Interaction with the BIRC3. Biomol Ther (Seoul) 2022; 30:380-388. [PMID: 35711139 PMCID: PMC9252879 DOI: 10.4062/biomolther.2022.063] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/22/2022] [Accepted: 05/28/2022] [Indexed: 11/23/2022] Open
Abstract
Snail is implicated in tumour growth and metastasis and is up-regulated in various human tumours. Although the role of Snails in epithelial-mesenchymal transition, which is particularly important in cancer metastasis, is well known, how they regulate tumour growth is poorly described. In this study, the possible molecular mechanisms of Snail in tumour growth were explored. Baculoviral inhibitor of apoptosis protein (IAP) repeat-containing protein 3 (BIRC3), a co-activator of cell proliferation during tumourigenesis, was identified as a Snail-binding protein via a yeast two-hybrid system. Since BIRC3 is important for cell survival, the effect of BIRC3 binding partner Snail on cell survival was investigated in ovarian cancer cell lines. Results revealed that Bax expression was activated, while the expression levels of anti-apoptotic proteins were markedly decreased by small interfering RNA (siRNA) specific for Snail (siSnail). siSnail, the binding partner of siBIRC3, activated the tumour suppressor function of p53 by promoting p53 protein stability. Conversely, BIRC3 could interact with Snail, for this reason, the possibility of BIRC3 involvement in EMT was investigated. BIRC3 overexpression resulted in a decreased expression of the epithelial marker and an increased expression of the mesenchymal markers. siSnail or siBIRC3 reduced the mRNA levels of matrix metalloproteinase (MMP)-2 and MMP-9. These results provide evidence that Snail promotes cell proliferation by interacting with BIRC3 and that BIRC3 might be involved in EMT via binding to Snail in ovarian cancer cells. Therefore, our results suggested the novel relevance of BIRC3, the binding partner of Snail, in ovarian cancer development.
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Affiliation(s)
- Seung Bae Rho
- Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
| | - Hyun-Jung Byun
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul/Goyang 04620, Republic of Korea
| | - Boh-Ram Kim
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul/Goyang 04620, Republic of Korea
| | - Chang Hoon Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul/Goyang 04620, Republic of Korea
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Danilova T, Belevich I, Li H, Palm E, Jokitalo E, Otonkoski T, Lindahl M. MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice. Diabetes 2019; 68:66-80. [PMID: 30305368 DOI: 10.2337/db17-1149] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 09/30/2018] [Indexed: 11/13/2022]
Abstract
Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of β-cell mass and insulin-dependent diabetes in mice. Similar to Manf-/- mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of pancreatic β-cell mass and for adult β-cell maintenance in mice. Detailed analysis of Pdx-1Cre+/- ::Manffl/fl mice revealed mosaic MANF expression in postnatal pancreata and a significant correlation between the number of MANF-positive β-cells and β-cell mass in individual mice. In vitro, recombinant MANF induced β-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from β-cells of adult MIP-1CreERT::Manffl/fl mice resulted in reduced β-cell mass and diabetes caused largely by β-cell ER stress and apoptosis, possibly accompanied by β-cell dedifferentiation and reduced rates of β-cell proliferation. Thus, MANF expression in adult mouse β-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress and inflammatory signaling pathways leading to β-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.
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Affiliation(s)
- Tatiana Danilova
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Ilya Belevich
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Huini Li
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Erik Palm
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Eija Jokitalo
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Timo Otonkoski
- Research Programs Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki, Helsinki, Finland
- Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland
| | - Maria Lindahl
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
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Danilova T, Lindahl M. Emerging Roles for Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) in Pancreatic Beta Cells and Diabetes. Front Physiol 2018; 9:1457. [PMID: 30386256 PMCID: PMC6198132 DOI: 10.3389/fphys.2018.01457] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 09/26/2018] [Indexed: 12/31/2022] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) was originally identified as a secreted trophic factor for dopamine neurons in vitro. It protects and restores damaged cells in rodent models of Parkinson's disease, brain and heart ischemia, spinocerebellar ataxia and retina in vivo. However, its exact mechanism of action is not known. MANF is widely expressed in most human and mouse organs with high levels in secretory tissues. Intracellularly, MANF localizes to the endoplasmic reticulum (ER) and ER stress increases it's expression in cells and tissues. Furthermore, increased MANF levels has been detected in the sera of young children with newly diagnosed Type 1 (T1D) diabetes and Type 2 (T2D) diabetic patients. ER stress is caused by the accumulation of misfolded and aggregated proteins in the ER. It activates a cellular defense mechanism, the unfolded protein response (UPR), a signaling cascade trying to restore ER homeostasis. However, if prolonged, unresolved ER stress leads to apoptosis. Unresolved ER stress contributes to the progressive death of pancreatic insulin-producing beta cells in both T1D and T2D. Diabetes mellitus is characterized by hyperglycemia, caused by the inability of the beta cells to maintain sufficient levels of circulating insulin. The current medications, insulin and antidiabetic drugs, alleviate diabetic symptoms but cannot reconstitute physiological insulin secretion which increases the risk of devastating vascular complications of the disease. Thus, one of the main strategies in improving current diabetes therapy is to define and validate novel approaches to protect beta cells from stress as well as activate their regeneration. Embryonic deletion of the Manf gene in mice led to gradual postnatal development of insulin-deficient diabetes caused by reduced beta cell proliferation and increased beta cell death due to increased and sustained ER stress. In vitro, recombinant MANF partly protected mouse and human beta cells from ER stress-induced beta cell death and potentiated mouse and human beta cell proliferation. Importantly, in vivo overexpression of MANF in the pancreas of T1D mice led to increased beta cell proliferation and decreased beta cell death, suggesting that MANF could be a new therapeutic candidate for beta cell protection and regeneration in diabetes.
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Affiliation(s)
- Tatiana Danilova
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Maria Lindahl
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
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Abstract
PURPOSE OF REVIEW Extranodal mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct clinical-pathological entity that can be distinguished from other lymphomas by a number of unique features, including their location in various extranodal sites, being preceded by chronic inflammatory or infection processes; a characteristic histopathological picture; and the presence of exclusive chromosomal translocations which increase MALT1 proteolytic activity to promote constitutive NF-κB signaling and eventually drive lymphomagenesis. RECENT FINDINGS This review explores the major molecular and cellular events that participate in MALT lymphoma pathogenesis, focusing on gastric MALT lymphoma as a model of chronic inflammation-induced tumor development. In addition, the pivotal roles of activated MALT1 protease, its substrate TNFAIP3/A20, and the MyD88 adaptor protein in abnormally triggering downstream NF-κB pathway are overviewed. These new insights provide a mechanistic basis for using novel therapies targeting MALT1 protease or IRAK4 kinase activities. Finally, the putative cellular origin of MALT lymphomas is also discussed. SUMMARY Over the last decade, unraveling the biological complexity of MALT lymphomas has shed light on the fundamental cellular and molecular aspects of the disease that are to be translated into clinical diagnostics and therapy.
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Chiarini A, Liu D, Armato U, Dal Prà I. Bcl10 crucially nucleates the pro-apoptotic complexes comprising PDK1, PKCζ and caspase-3 at the nuclear envelope of etoposide-treated human cervical carcinoma C4-I cells. Int J Mol Med 2015. [PMID: 26202083 DOI: 10.3892/ijmm.2015.2290] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Protein kinase (PK)Cζ signaling at various subcellular levels affects cell survival, differentiation, growth and/or apoptosis. However, the mechanisms modulating PKCζ activity at the nuclear membrane (NM) are not yet fully understood. Previously, we demonstrated that PKCζ interacts with the B‑cell lymphoma 10 (Bcl10) protein at the NM of human cervical carcinoma (HCC) C4‑I cells. In the present study, we aimed to further clarify the interactions between PKCζ, Bcl10 and other proteins co-immunoprecipitated from NMs isolated from untreated and etoposide (also known as VP‑16; 2.0 µg/ml)‑treated C4‑I cells using biochemical and proteomics analyses. Aside from the Bcl10 protein, 3‑phosphoinositide‑dependent protein kinase‑1 (PDK1) also co-immunoprecipitated with PKCζ from NMs of C4‑I cells, indicating the assembly of a heterotrimeric complex, which increased with time in VP‑16‑exposed cells, as did the activity of PDK1‑phosphorylated‑PKCζ. In turn, PKCζ‑phosphorylated‑Bcl10 straddled an enlarged complex which comprised caspase‑3. Subsequently, activity‑enhanced caspase‑3 cleaved and inactivated PKCζ. Finally, the suppression of Bcl10 using specific siRNA or lentiviral transduction prevented the increase in the PDK1•PKCζ association, the increase in the activity of PKCζ and caspase‑3, as well as the caspase‑3‑mediated PKCζ proteolysis and inactivation from occurring at the NMs of the VP‑16‑exposed C4‑I cells. Our observations provide evidence that Bcl10 acts as a pivotal pro-apoptotic protein which crucially nucleates complexes comprising PDK1, PKCζ and active caspase‑3 at the NMs of VP‑16‑exposed C4‑I cells. Hence, our data suggest that Bcl10 and PKCζ are potential therapeutic targets in the treatment of HCC.
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Affiliation(s)
- Anna Chiarini
- Histology and Embryology Section, Department of Life and Reproduction Sciences, University of Verona Medical School, I‑37134 Verona, Venetia, Italy
| | - Daisong Liu
- Chongqing Key Laboratory for Disease Proteomics, Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Ubaldo Armato
- Histology and Embryology Section, Department of Life and Reproduction Sciences, University of Verona Medical School, I‑37134 Verona, Venetia, Italy
| | - Ilaria Dal Prà
- Histology and Embryology Section, Department of Life and Reproduction Sciences, University of Verona Medical School, I‑37134 Verona, Venetia, Italy
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Mazzone P, Scudiero I, Ferravante A, Paolucci M, D’Andrea LE, Varricchio E, Telesio G, De Maio C, Pizzulo M, Zotti T, Reale C, Vito P, Stilo R. Functional characterization of zebrafish (Danio rerio) Bcl10. PLoS One 2015; 10:e0122365. [PMID: 25849213 PMCID: PMC4388727 DOI: 10.1371/journal.pone.0122365] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 02/15/2015] [Indexed: 12/25/2022] Open
Abstract
The complexes formed by BCL10, MALT1 and specific members of the family of CARMA proteins (CBM complex), have recently focused much attention because they represent a central hub regulating activation of the transcription factor NF-κB following various cellular stimulations. In this manuscript, we report the functional characterization of a Danio rerio 241 amino acids polypeptide ortholog of the Caspase recruiting domain (CARD)-containing protein BCL10. Biochemical studies show that zebrafish Bcl10 (zBcl10) dimerizes and binds to components of the CBM complex. Fluorescence microscopy observations demonstrate that zBcl10 forms cytoplasmic filaments similar to that formed by human BCL10 (hBCL10). Functionally, in human cells zBcl10 is more effective in activating NF-κB compared to hBCL10, possibly due to the lack of carboxy-terminal inhibitory serine residues present in the human protein. Also, depletion experiments carried out through expression of short hairpin RNAs targeting hBCL10 indicate that zBcl10 can functionally replace the human protein. Finally, we show that the zebrafish cell line PAC2 is suitable to carry out reporter assays for monitoring the activation state of NF- kB transcription factor. In conclusion, this work shows that zebrafish may excellently serve as a model organism to study complex and intricate signal transduction pathways, such as those that control NF-κB activation.
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Affiliation(s)
| | | | | | - Marina Paolucci
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port’ Arsa 10, Benevento, Italy
| | | | - Ettore Varricchio
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port’ Arsa 10, Benevento, Italy
| | | | | | | | - Tiziana Zotti
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port’ Arsa 10, Benevento, Italy
| | - Carla Reale
- Biogem, Via Camporeale, Ariano Irpino (AV), Italy
| | - Pasquale Vito
- Biogem, Via Camporeale, Ariano Irpino (AV), Italy
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port’ Arsa 10, Benevento, Italy
- * E-mail:
| | - Romania Stilo
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port’ Arsa 10, Benevento, Italy
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Mazzone P, Scudiero I, Coccia E, Ferravante A, Paolucci M, D'Andrea EL, Varricchio E, Pizzulo M, Reale C, Zotti T, Vito P, Stilo R. Functional characterization of a BCL10 isoform in the rainbow trout Oncorhynchus mykiss. FEBS Open Bio 2015; 5:175-81. [PMID: 25834783 PMCID: PMC4372615 DOI: 10.1016/j.fob.2015.01.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 01/29/2015] [Accepted: 01/30/2015] [Indexed: 01/01/2023] Open
Abstract
The complexes formed by BCL10, MALT1 and CARMA proteins are key regulators of NF-κB activation. We report the functional characterization of tBCL10, a BCL10 isoform from the trout Oncorhynchus mykiss. tBCL10 can functionally replace the human protein. The rainbow trout Oncorhynchus mykiss can serve as a model organism to study this pathway. The complexes formed by BCL10, MALT1 and members of the family of CARMA proteins have recently been the focus of much attention because they represent a key mechanism for regulating activation of the transcription factor NF-κB. Here, we report the functional characterization of a novel isoform of BCL10 in the trout Oncorhynchus mykiss, which we named tBCL10. tBCL10 dimerizes, binds to components of the CBM complex and forms cytoplasmic filaments. Functionally, tBCL10 activates NF-κB transcription factor and is inhibited by the deubiquitinating enzyme A20. Finally, depletion experiments indicate that tBCL10 can functionally replace the human protein. This work demonstrates the evolutionary conservation of the mechanism of NF-κB activation through the CBM complex, and indicates that the rainbow trout O.mykiss can serve as a model organism to study this pathway.
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Affiliation(s)
| | | | - Elena Coccia
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port' Arsa 10, Benevento, Italy
| | | | - Marina Paolucci
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port' Arsa 10, Benevento, Italy
| | | | - Ettore Varricchio
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port' Arsa 10, Benevento, Italy
| | | | - Carla Reale
- Biogem, Via Camporeale, Ariano Irpino (AV), Italy
| | - Tiziana Zotti
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port' Arsa 10, Benevento, Italy
| | - Pasquale Vito
- Biogem, Via Camporeale, Ariano Irpino (AV), Italy ; Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port' Arsa 10, Benevento, Italy
| | - Romania Stilo
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port' Arsa 10, Benevento, Italy
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Kozanoglu I, Yandim MK, Cincin ZB, Ozdogu H, Cakmakoglu B, Baran Y. New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma. J Cancer Res Clin Oncol 2013; 139:327-35. [PMID: 23080133 DOI: 10.1007/s00432-012-1331-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Accepted: 10/02/2012] [Indexed: 10/27/2022]
Abstract
PURPOSE Propranolol, a non-selective β-adrenergic receptor blocker, has been used for the treatment of the patients with hypertension for more than 50 years. There are several in vitro and in vivo evidences that β-adrenergic receptor antagonists inhibit proliferation and angiogenesis and also increase apoptosis in breast, skin, and colon cancers. The aim of this study was to investigate the cytotoxic and apoptotic effects of propranolol and the genes involved in propranolol-induced apoptosis in multiple myeloma cells. METHODS Time-dependent antiproliferation and apoptotic effects of propranolol were subsequently determined by MTT cell proliferation assay, changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP), and also the localization of phosphatidylserine in the plasma membrane. Changes in expression levels of NF-ΚB pathway were examined by qRT-PCR array. RESULTS IC50 values of propranolol on U266 cells were calculated as 141, 100, and 75 μM after 24-, 48-, and 72-h propranolol exposure, respectively. There were significant increases in caspase-3 activity, loss of MMP, and increases in apoptotic cell population in response to propranolol in U266 cells in a time- and dose-dependent manner. There were increases in expression levels of BCL10, TRAF family members, interleukins, TLR1-4, TNFRSF10B, NF-κB, and the inhibitors of NF-κB genes, and significant decreases in expression levels of Bcl-2 in response to propranolol treatment were observed. CONCLUSION These results revealed that propranolol has antiproliferative and apoptotic effects on multiple myeloma cells. Being supported with in vivo analyses, propranolol can be a good and economical way to treat multiple myeloma patients.
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Affiliation(s)
- Ilknur Kozanoglu
- Adana Adult Bone Marrow Center, Cell Processing Unit, Baskent University, Ankara, Turkey
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Chiarini A, Marconi M, Pacchiana R, Dal Prà I, Wu J, Armato U. Role-Shifting PKCζ Fosters Its Own Proapoptotic Destruction by Complexing with Bcl10 at the Nuclear Envelope of Human Cervical Carcinoma Cells: A Proteomic and Biochemical Study. J Proteome Res 2012; 11:3996-4012. [DOI: 10.1021/pr3000464] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Anna Chiarini
- Histology & Embryology Unit, Department of Life & Reproduction Sciences, University of Verona Medical School, Verona, I-37134, Italy
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Wang HY, Lin CY, Chien CC, Kan WC, Tian YF, Liao PC, Wu HY, Su SB. Impact of uremic environment on peritoneum: a proteomic view. J Proteomics 2012; 75:2053-63. [PMID: 22266485 DOI: 10.1016/j.jprot.2012.01.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Revised: 11/14/2011] [Accepted: 01/07/2012] [Indexed: 01/29/2023]
Abstract
Peritoneal morphology and function are abnormal in uremia patients, but the contributing mechanisms are unclear. Here we attempted to characterize the protein targets that may be related to peritoneal change in patients with uremia and have not exposed to peritoneal dialysis fluid. Protein profiles of peritoneal fluids collected from patients with uremia and patients with normal renal function receiving laparoscopic cholecystectomy were displayed by two-dimensional gel electrophoresis (2-DE). Altered protein spots were excised and subjected to tryptic digestion followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Sixteen 2-DE protein spots were altered between two groups. Western blots confirmed that kininogen-1, apoptosis inhibitor 2, cat eye syndrome critical region protein 1, and apolipoprotein A-I had higher expression levels in the uremia samples. In contrast, synaptic vesicle 2-related protein, glial fibrillary acidic protein, and envelope glycoprotein (C2-V5 region) showed lower levels. The increased expression may result from a change in the permeability of the peritoneal membrane to middle-sized proteins or peritoneal inflammation with proteins sloughing off. All the identified proteins may provide a novel understanding of peritoneal changes caused by uremic toxins and may function as biomarkers or drug targets.
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Affiliation(s)
- Hsien-Yi Wang
- Department of Nephrology, Chi-Mei Medical Center, Tainan 710, Taiwan
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Kuo SH, Weng WH, Chen ZH, Hsu PN, Wu MS, Lin CW, Jeng HJ, Yeh KH, Tsai HJ, Chen LT, Cheng AL. Establishment of a novel MALT lymphoma cell line, ma-1, from a patient with t(14;18)(q32;q21)-positive Helicobacter Pylori-Independent Gastric MALT Lymphoma. Genes Chromosomes Cancer 2011; 50:908-21. [PMID: 21837708 DOI: 10.1002/gcc.20910] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Accepted: 06/27/2011] [Indexed: 01/27/2023] Open
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Abstract
Heavy chain diseases (HCDs) are B-cell proliferative disorders characterized by the production of monoclonal, incomplete, immunoglobulin (Ig) heavy chains (HCs) without associated light chains (LCs). These abnormal HCs are produced as a consequence of HC gene alterations in the neoplastic B cells. HC gene alterations will also impact on surface HC, which is part of the B-cell receptor (BCR), a crucial player in lymphocyte activation by antigen. The selective advantage conferred to mutant cells by abnormal BCR without an antigen-binding domain may be explained by activation of ligand-independent signaling, in analogy to what has been shown for mutated oncogenic growth factor receptors. Here we review data obtained from mouse models showing abnormal, constitutive activity of HCD-BCR, and we discuss the possible mechanism involved, namely, aberrant spontaneous self-aggregation. This self-aggregation might occur as a consequence of escape from the chaperone immunoglobulin binding protein (BiP) and from the anti-aggregation effect of LC association. The concept of misfolding-induced signaling elaborated here may extend to other pathologies termed conformational diseases.
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Yu H, Liu F, Ramesh BP. Automatic figure ranking and user interfacing for intelligent figure search. PLoS One 2010; 5:e12983. [PMID: 20949102 PMCID: PMC2951344 DOI: 10.1371/journal.pone.0012983] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2010] [Accepted: 08/20/2010] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Figures are important experimental results that are typically reported in full-text bioscience articles. Bioscience researchers need to access figures to validate research facts and to formulate or to test novel research hypotheses. On the other hand, the sheer volume of bioscience literature has made it difficult to access figures. Therefore, we are developing an intelligent figure search engine (http://figuresearch.askhermes.org). Existing research in figure search treats each figure equally, but we introduce a novel concept of "figure ranking": figures appearing in a full-text biomedical article can be ranked by their contribution to the knowledge discovery. METHODOLOGY/FINDINGS We empirically validated the hypothesis of figure ranking with over 100 bioscience researchers, and then developed unsupervised natural language processing (NLP) approaches to automatically rank figures. Evaluating on a collection of 202 full-text articles in which authors have ranked the figures based on importance, our best system achieved a weighted error rate of 0.2, which is significantly better than several other baseline systems we explored. We further explored a user interfacing application in which we built novel user interfaces (UIs) incorporating figure ranking, allowing bioscience researchers to efficiently access important figures. Our evaluation results show that 92% of the bioscience researchers prefer as the top two choices the user interfaces in which the most important figures are enlarged. With our automatic figure ranking NLP system, bioscience researchers preferred the UIs in which the most important figures were predicted by our NLP system than the UIs in which the most important figures were randomly assigned. In addition, our results show that there was no statistical difference in bioscience researchers' preference in the UIs generated by automatic figure ranking and UIs by human ranking annotation. CONCLUSION/SIGNIFICANCE The evaluation results conclude that automatic figure ranking and user interfacing as we reported in this study can be fully implemented in online publishing. The novel user interface integrated with the automatic figure ranking system provides a more efficient and robust way to access scientific information in the biomedical domain, which will further enhance our existing figure search engine to better facilitate accessing figures of interest for bioscientists.
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Affiliation(s)
- Hong Yu
- Department of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America.
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15
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Kasten-Jolly J, Heo Y, Lawrence DA. Impact of developmental lead exposure on splenic factors. Toxicol Appl Pharmacol 2010; 247:105-15. [PMID: 20542052 DOI: 10.1016/j.taap.2010.06.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Revised: 05/25/2010] [Accepted: 06/03/2010] [Indexed: 01/09/2023]
Abstract
Lead (Pb) is known to alter the functions of numerous organ systems, including the hematopoietic and immune systems. Pb can induce anemia and can lower host resistance to bacterial and viral infections. The anemia is due to Pb's inhibition of hemoglobin synthesis and Pb's induction of membrane changes, leading to early erythrocyte senescence. Pb also increases B-cell activation/proliferation and skews T-cell help (Th) toward Th2 subset generation. The specific mechanisms for many of the Pb effects are, as yet, not completely understood. Therefore, we performed gene expression analysis, via microarray, on RNA from the spleens of developmentally Pb-exposed mice, in order to gain further insight into these Pb effects. Splenic RNA microarray analysis indicated strong up-regulation of genes coding for proteolytic enzymes, lipases, amylase, and RNaseA. The data also showed that Pb affected the expression of many genes associated with innate immunity. Analysis of the microarray results via GeneSifter software indicated that Pb increased apoptosis, B-cell differentiation, and Th2 development. Direct up-regulation by Pb of expression of the gene encoding the heme-regulated inhibitor (HRI) suggested that Pb can decrease erythropoiesis by blocking globin mRNA translation. Pb's high elevation of digestive/catabolizing enzymes could generate immunogenic self peptides. With Pb's potential to induce new self-peptides and to enhance the expression of caspases, cytokines, and other immunomodulators, further evaluation of Pb's involvement in autoimmune phenomena, especially Th2-mediated autoantibody production, and alteration of organ system activities is warranted.
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Affiliation(s)
- Jane Kasten-Jolly
- Laboratory of Clinical and Experimental Endocrinology and Immunology, Wadsworth Center, Albany, NY 12201-0509, USA
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16
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Briones J, Moga E, Espinosa I, Vergara C, Alvarez E, Villa J, Bordes R, Delgado J, Prat J, Sierra J. Bcl-10 protein highly correlates with the expression of phosphorylated p65 NF-kappaB in peripheral T-cell lymphomas and is associated with clinical outcome. Histopathology 2009; 54:478-85. [PMID: 19309400 DOI: 10.1111/j.1365-2559.2009.03250.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS In T cells, protein kinase C (PKC) theta plays a major role in T-cell receptor (TCR)-mediated activation of a novel nuclear factor (NF)-kappaB pathway that involves phosphorylation of p65 at serine 536 (Pp65(Ser536)). Bcl-10 acts along the same pathway downstream of PKC theta to activate NF-kappaB. The aim was to investigate the relationship between the expression of PKC theta, Bcl-10 and P-p65(Ser536) proteins and their prognostic significance in peripheral T-cell lymphomas (PTCLs). METHODS AND RESULTS Paraffin-embedded tissues from 30 patients with PTCLs treated with curative intention were evaluated retrospectively. Expression of PKC theta, Bcl-10 and P-p65(Ser536) proteins was assessed using immunohistochemistry. Expression of PKC theta was detected in 22 of 30 cases (73%), Bcl-10 in 20 of 30 (67%) and P-p65(Ser536) in 21 of 30 (70%). Bcl-10+ tumours were associated with PKC theta (18 of 22) (P < 0.0001) and Pp65Ser536 (19 of 21) expression (P < 0.0001). Patients with Bcl-10+ or P-p65(Ser536+) tumours fared better, with a 5-year overall survival of 48 and 45%, respectively, versus 0% for negative tumours (P = 0.029 and P = 0.04, respectively). CONCLUSIONS Bcl-10 is expressed in PTCLs, correlates with PKC theta and Pp65(Ser536) expression and seems to be associated with better survival.
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Affiliation(s)
- Javier Briones
- Departments of Clinical Haematology and Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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17
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Abstract
The activation of T cells is vital to the successful elimination of pathogens, but can also have a deleterious role in autoimmunity and transplant rejection. Various signalling pathways are triggered by the T-cell receptor; these have key roles in the control of the T-cell response and represent interesting targets for therapeutic immunomodulation. Recent findings define MALT1 (mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1) as a protein with proteolytic activity that controls T-cell activation by regulating key molecules in T-cell-receptor-induced signalling pathways.
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18
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Du MQ. MALT lymphoma : recent advances in aetiology and molecular genetics. J Clin Exp Hematop 2008; 47:31-42. [PMID: 18040143 DOI: 10.3960/jslrt.47.31] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Mucosa-associated lymphoid tissue (MALT) lymphoma is a common low grade B-cell lymphoma arising from a background of chronic inflammatory disease at a number of mucosal sites. Those originating in the stomach are causatively linked to Helicobacter pylori infection and eradication of the bacterium with antibiotics leads to long-term complete regression of the lymphoma in aproximately 70% of cases. Now, there is further evidence of linking Campylobacter jejuni, Borrelia burgdorferi and Chlamydia psittaci infection with immunoproliferative small intestine disease, MALT lymphoma of the skin and ocular adnexa respectively. t(11;18)/API2-MALT1, t(1;14)/IGH-BCL10, t(14;18)/IGH-MALT1 and t(3;14)/IGH-FOXP1 occur at considerably variable incidences in MALT lymphomas of different sites. The first three chromosome translocations are specifically associated with the MALT lymphoma entity and the oncogenic products of these translocations have been shown to target a common molecular pathway, i.e. the nuclear factor-kappaB pathway. Here, I review the recent advances in our understanding of the association of microbial pathogens with MALT lymphoma of various sites and the molecular genetics underlying the lymphoma development.
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Affiliation(s)
- Ming-Qing Du
- Department of Pathology, University of Cambridge, Cambridge, UK.
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19
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Bhattacharyya S, Borthakur A, Pant N, Dudeja PK, Tobacman JK. Bcl10 mediates LPS-induced activation of NF-kappaB and IL-8 in human intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2007; 293:G429-37. [PMID: 17540779 DOI: 10.1152/ajpgi.00149.2007] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Lipopolysaccharide (LPS) is recognized as an inducer of the inflammatory response associated with gram-negative sepsis and systemic inflammatory response syndrome. LPS induction proceeds through Toll-like receptor (TLR) in immune cells and intestinal epithelial cells (IEC). This report presents the first identification of Bcl10 (B-cell CLL/lymphoma 10) as a mediator of the LPS-induced activation of IL-8 in human IEC. Bcl10 is a caspase-recruitment domain-containing protein, associated with constitutive activation of NF-kappaB in MALT (mucosa-associated lymphoid tissue) lymphomas. The normal human IEC line NCM460, normal primary human colonocytes, and ex vivo human colonic tissue were exposed to 10 ng/ml of LPS for 2-6 h. Effects on Bcl10, phospho-IkappaBalpha, NF-kappaB, and IL-8 were determined by Western blot, ELISA, immunohistochemistry, and confocal microscopy. Effects of Bcl10 silencing by small-interfering RNA (siRNA), TLR4 blocking antibody, TLR4 silencing by siRNA, and an IL-1 receptor-associated kinase (IRAK)-1/4 inhibitor on LPS-induced activation were examined. Following Bcl10 silencing, LPS-induced increases in NF-kappaB, IkappaBalpha, and IL-8 were significantly reduced (P < 0.001). Increasing concentrations of LPS were associated with higher concentrations of Bcl10 protein when quantified by ELISA, and the association between LPS exposure and increased Bcl10 was also demonstrated by Western blot, immunohistochemistry, and confocal microscopy. Exposure to TLR4 antibody, TLR4 siRNA, or an IRAK-1/4 inhibitor eliminated the LPS-induced increases in Bcl10, NF-kappaB, and IL-8. Identification of Bcl10 as a mediator of LPS-induced activation of NF-kappaB and IL-8 in normal human IEC provides new insight into mechanisms of epithelial inflammation and new opportunities for therapeutic intervention.
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Affiliation(s)
- Sumit Bhattacharyya
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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20
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Rueda D, Gaide O, Ho L, Lewkowicz E, Niedergang F, Hailfinger S, Rebeaud F, Guzzardi M, Conne B, Thelen M, Delon J, Ferch U, Mak TW, Ruland J, Schwaller J, Thome M. Bcl10 controls TCR- and FcgammaR-induced actin polymerization. THE JOURNAL OF IMMUNOLOGY 2007; 178:4373-84. [PMID: 17371994 DOI: 10.4049/jimmunol.178.7.4373] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Bcl10 plays an essential role in the adaptive immune response, because Bcl10-deficient lymphocytes show impaired Ag receptor-induced NF-kappaB activation and cytokine production. Bcl10 is a phosphoprotein, but the physiological relevance of this posttranslational modification remains poorly defined. In this study, we report that Bcl10 is rapidly phosphorylated upon activation of human T cells by PMA/ionomycin- or anti-CD3 treatment, and identify Ser(138) as a key residue necessary for Bcl10 phosphorylation. We also show that a phosphorylation-deficient Ser(138)/Ala mutant specifically inhibits TCR-induced actin polymerization yet does not affect NF-kappaB activation. Moreover, silencing of Bcl10, but not of caspase recruitment domain-containing MAGUK protein-1 (Carma1) induces a clear defect in TCR-induced F-actin formation, cell spreading, and conjugate formation. Remarkably, Bcl10 silencing also impairs FcgammaR-induced actin polymerization and phagocytosis in human monocytes. These results point to a key role of Bcl10 in F-actin-dependent immune responses of T cells and monocytes/macrophages.
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Affiliation(s)
- Daniel Rueda
- Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, Epalinges, Switzerland
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21
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Rawlings DJ, Sommer K, Moreno-García ME. The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat Rev Immunol 2006; 6:799-812. [PMID: 17063183 DOI: 10.1038/nri1944] [Citation(s) in RCA: 150] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The recognition of antigen by B- or T-cell receptors initiates an intracellular signalling cascade that results in the nuclear translocation and activation of the transcription factor nuclear factor-kappaB (NF-kappaB). NF-kappaB is an important regulator of lymphocyte development and function, and its dysregulation is associated with many immune disorders. Defining the mechanisms that transmit signals from the antigen receptor to NF-kappaB is therefore an important goal for immunologists. In this Review, we merge information gleaned from research of the innate immune system with what we know about antigen-receptor signals in the adaptive immune system, to propose a cohesive model of how antigen receptors activate NF-kappaB.
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Affiliation(s)
- David J Rawlings
- Department of Immunology, Childrens Hospital & Regional Medical Centre, 307 Westlake Avenue North, Suite 300, Seattle, Washington 98109, USA.
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22
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Nakagawa M, Seto M, Hosokawa Y. Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein. Leukemia 2006; 20:929-36. [PMID: 16572204 DOI: 10.1038/sj.leu.2404192] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF-kappaB) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF-kappaB-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF-kappaB activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF-kappaB-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10.
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Affiliation(s)
- M Nakagawa
- Division of Molecular Medicine, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan
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23
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Zhou Y, Ye H, Martin-Subero JI, Hamoudi R, Lu YJ, Wang R, Siebert R, Shipley J, Isaacson PG, Dogan A, Du MQ. Distinct comparative genomic hybridisation profiles in gastric mucosa-associated lymphoid tissue lymphomas with and without t(11;18)(q21;q21). Br J Haematol 2006; 133:35-42. [PMID: 16512826 DOI: 10.1111/j.1365-2141.2006.05969.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
t(11;18)(q21;q21) occurs specifically in mucosa-associated lymphoid tissue (MALT) lymphoma and the translocation generates a functional API2-MALT1 fusion product that activates nuclear factor (NF)kappaB. t(11;18) positive lymphomas usually lack the chromosomal aberrations and microsatellite alterations frequently seen in the translocation-negative MALT lymphomas. To further understand their genetic differences, we investigated gastric MALT lymphomas with and without t(11;18) by comparative genomic hybridisation. In general, both chromosomal gains and losses were far more frequent in t(11;18)-negative (median = 3.4 imbalances) than t(11;18)-positive cases (median = 1.6 imbalances), with gains being more frequent than losses. Recurrent chromosomal gains involving whole or major parts of a chromosome were seen for chromosomes 3, 12, 18 and 22 (23%, 19%, 19% and 27% respectively). Discrete recurrent chromosomal gains were found at 9q34 (11/26 = 42%). Bioinformatic analysis of genes mapping to 9q34 revealed potential targets. Among them, TRAF2 and CARD9 are known interaction partners of BCL10, playing a role in NFkappaB activation. Interphase fluorescent in situ hybridisation confirmed genomic gain of the TRAF2, CARD9 and MALT1 loci in 5/6 and 2/2 cases showing chromosomal gains at 9q34 and 18q21 respectively. The results further highlight the genetic difference between MALT lymphomas with and without t(11;18). Moreover, our findings suggest that genomic gain of genes that modulate NFkappaB activation, such as MALT1, TRAF2 and CARD9, may play a role in the pathogenesis of the translocation-negative MALT lymphoma.
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MESH Headings
- Adaptor Proteins, Signal Transducing/genetics
- CARD Signaling Adaptor Proteins
- Caspases
- Chromosome Mapping
- Chromosomes, Human, Pair 11
- Chromosomes, Human, Pair 18
- Computational Biology
- Gastric Mucosa/pathology
- Genomics
- Humans
- In Situ Hybridization, Fluorescence
- Interphase
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/pathology
- Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
- Neoplasm Proteins/genetics
- Oncogene Proteins, Fusion/genetics
- Signal Processing, Computer-Assisted
- Stomach Neoplasms/genetics
- Stomach Neoplasms/pathology
- TNF Receptor-Associated Factor 2/genetics
- Translocation, Genetic
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Affiliation(s)
- Yuanping Zhou
- Division of Molecular Histopathology, Department of Pathology, University of Cambridge, UK
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24
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Nakamura S, Nakamura S, Matsumoto T, Yada S, Hirahashi M, Suekane H, Yao T, Goda K, Iida M. Overexpression of caspase recruitment domain (CARD) membrane-associated guanylate kinase 1 (CARMA1) and CARD9 in primary gastric B-cell lymphoma. Cancer 2005; 104:1885-93. [PMID: 16177990 DOI: 10.1002/cncr.21421] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Although caspase recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1) and CARD9 play important roles in lymphocyte activation, the significance of CARMA1 and CARD9 in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma remains to be elucidated. METHODS By using reverse transcription-polymerase chain reaction analysis, the expression levels of mRNA of CARMA1, CARD9, Bcl10, and the apoptosis inhibitor 2 (API2)-MALT1 chimeric transcript were determined in tissue specimens from 65 patients with primary gastric B-cell lymphoma (43 patients with low-grade MALT lymphoma, 16 patients with MALT lymphoma plus diffuse large B-cell lymphoma [DLBL], and 6 patients with DLBL without MALT lymphoma) and in tissue specimens from 18 patients with chronic gastritis. The expression levels of CARMA1 and BCL10 were examined immunohistochemically in 30 patients with lymphoma. RESULTS CARMA1 mRNA was detected in 55% of lymphoma patients but in only 17% of chronic gastritis patients. The positive rates for CARD9, Bcl10, and API2-MALT1 chimeric transcript in the lymphoma patients were 48%, 98%, and 8%, respectively, whereas the 3 molecules were not detected in any specimens from patients with chronic gastritis. The expression of CARMA1 and CARD9 was frequent in the Helicobacter pylori-negative patients (100% and 86%, respectively), in the API2-MALT1 chimeric transcript-positive patients (100% and 100%, respectively), and in the specimens from patients who did not respond to H. pylori eradication (76% and 71%, respectively). In addition, CARMA1 expression was positive more frequently in patients of DLBL without MALT lymphoma (100%) than in patients of MALT lymphoma (51%). CARMA1 protein expression was correlated significantly with the expression of CARMA1 mRNA and also with the expression of nuclear BCL10. CONCLUSIONS The overexpression of CARMA1 and CARD9 presumably is associated with the development or progression of gastric B-cell lymphoma, especially among patients who have disease in which the pathogenesis is not related to H. pylori.
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Affiliation(s)
- Shigeo Nakamura
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Japan
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25
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Tian MT, Gonzalez G, Scheer B, DeFranco AL. Bcl10 can promote survival of antigen-stimulated B lymphocytes. Blood 2005; 106:2105-12. [PMID: 15878976 PMCID: PMC1895143 DOI: 10.1182/blood-2004-04-1248] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
To understand the nature of negative responses through the B-cell antigen receptor (BCR), we have screened an expression cDNA library for the ability to block BCR-induced growth arrest and apoptosis in the immature B-cell line, WEHI-231. We isolated multiple copies of full-length, unmutated Bcl10, a signaling adaptor molecule encoded by a gene found to translocate to the immunoglobulin heavy chain (IgH) locus in some mucosa-associated lymphoid tissue (MALT) lymphomas. A conditionally active form of B-cell lymphoma 10 (Bcl10) protected WEHI-231 cells from BCR-induced apoptosis upon activation. Induction of Bcl10 activity caused rapid activation of nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK), but not activation of extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein (MAP) kinases. These results support genetic and biochemical experiments that have implicated Bcl10 and its binding partners Carma1 and MALT1 in mediating the ability of the BCR to activate NF-kappaB. The ability of Bcl10 expression to prevent BCR-induced growth arrest and apoptosis of WEHI-231 cells was dependent on NF-kappaB activation. Finally, overexpression of Bcl10 in primary B cells activated ex vivo promoted the survival of these cells after removal of activating stimuli. Taken together these results support the hypothesis that enhanced BCL10 expression caused by translocation to the IGH locus can promote formation of MALT lymphomas.
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Affiliation(s)
- Maoxin Tim Tian
- Department of Microbiology and Immunology, UCSF, 513 Parnassus Ave, San Francisco, CA 94143-0414, USA
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26
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Isaacson PG, Du MQ. Gastrointestinal lymphoma: where morphology meets molecular biology. J Pathol 2005; 205:255-74. [PMID: 15643667 DOI: 10.1002/path.1703] [Citation(s) in RCA: 128] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Primary gastrointestinal lymphomas are best exemplified by mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach and enteropathy-type T-cell lymphoma (ETL). Both lymphomas were initially recognized on morphological grounds and their identification as distinct clinicopathological entities has subsequently been vindicated following integrated immunophenotypic, molecular, and cellular biological investigations. Delineation of the phenotypic, molecular, and biological properties of these lymphomas at various clinicopathological stages of their development has also provided critical information for the clinical management of patients with these diseases. Here, the histopathology and recent advances in phenotypic and molecular characterization of gastric MALT lymphoma and ETL and their applications in diagnosis and clinical management are reviewed.
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Affiliation(s)
- Peter G Isaacson
- Department of Histopathology, University College London, London WC1E 6JJ, UK.
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27
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Yu LL, Yu HG, Yu JP, Luo HS, Xu XM, Li JH. Nuclear factor-kB p65 (RelA) transcription factor is constitutively activated in human colorectal carcinoma tissue. World J Gastroenterol 2004; 10:3255-60. [PMID: 15484295 PMCID: PMC4572290 DOI: 10.3748/wjg.v10.i22.3255] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Activation of transcription factor nuclear factor-κB (NF-κB) has been shown to play a role in cell proliferation, apoptosis, cytokine production, and oncogenesis. The purpose of this study was to determine whether NF-κB was constitutively activated in human colorectal tumor tissues and, if so, to determine the role of NF-κB in colorectal tumorigenesis, and furthermore, to determine the association of RelA expression with tumor cell apoptosis and the expression of Bcl-2 and Bcl-xL.
METHODS: Paraffin sections of normal epithelial, adenomatous and adenocarcinoma tissues were analysed immunohisto- chemically for expression of RelA, Bcl-2 and Bcl-xL proteins. Electrophoretic mobility shift assay (EMSA) was used to confirm the increased nuclear translocation of RelA in colorectal tumor tissues. The mRNA expressions of Bcl-2 and Bcl-xL were determined by reverse transcription polymerase chain reaction (RT-PCR) analysis. Apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate fluorescence nick end labeling (TUNEL) method.
RESULTS: The activity of NF-κB was significantly higher in adenocarcinoma tissue in comparison with that in adenomatous and normal epithelial tissues. The apoptotic index (AI) significantly decreased in the transition from adenoma to adenocarcinoma. Meanwhile, the expressions of Bcl-2 and Bcl-xL protein and their mRNAs were significantly higher in adenocarcinoma tissues than that in adenomatous and normal epithelial tissues.
CONCLUSION: NF-κB may inhibit apoptosis via enhancing the expression of the apoptosis genes Bcl-2 and Bcl-xL. And the increased expression of RelA/nuclear factor-κB plays an important role in the pathogenesis of colorectal carcinoma.
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Affiliation(s)
- Liang-Liang Yu
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan 430060, Hubei Province, China.
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28
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Affiliation(s)
- Peter G Isaacson
- Department of Histopathology, Royal Free and University College Medical School, University College London, Rockefeller Building, University Street, London WC1E 6JJ, UK.
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29
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Wu MS, Chen LT, Shun CT, Huang SP, Chiu HM, Wang HP, Lin MT, Cheng AL, Lin JT. Promoter polymorphisms of tumor necrosis factor-alpha are associated with risk of gastric mucosa-associated lymphoid tissue lymphoma. Int J Cancer 2004; 110:695-700. [PMID: 15146559 DOI: 10.1002/ijc.20199] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Genes involved in regulating antimicrobial immunity and inflammation may modulate the risk of Helicobacter pylori-associated diseases. IL-1 and TNF-alpha are major cytokines detected in H. pylori-infected tissues. We aimed to determine the role of gene polymorphisms for these cytokines and their receptors in 2 distinct H. pylori-related gastric malignancies, adenocarcinoma (GAC) and maltoma. Genotyping for IL-1beta (-31 C/T, -511 C/T), TNF-alpha (-238 G/A, -308 G/A, -857 C/T, -863 C/A, -1031 T/C), TNFR1 (-383 A/C) and TNFR2 (196 G/T) was undertaken for 70 patients with maltoma and 204 patients with noncardia GAC and compared to 210 unrelated healthy controls. Genotype frequencies showed no differences among patients with GAC or maltoma and controls for IL-1beta, TNFR1 or TNFR2. The TNF-alpha -857 T variant was significantly underrepresented in maltoma compared to controls (6.4% vs. 14.3%, p = 0.018), conferring a 3-fold decrease in risk (OR = 0.33, 95% CI 0.15-0.75). Comparison of allele frequencies between GAC and controls failed to show any statistical significance for TNF-alpha polymorphisms. We concluded that TNF-alpha -857 T itself or a neighboring gene may modify the risk of maltoma. The differences in genetic background as well as divergent clinicopathologic features between GAC and maltoma support the notion that fundamental mechanistic differences exist in these 2 well-defined H. pylori-related malignancies.
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Affiliation(s)
- Ming-Shiang Wu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
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30
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Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 2004; 14:289-301. [PMID: 15125833 DOI: 10.1016/s1097-2765(04)00236-9] [Citation(s) in RCA: 565] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2004] [Revised: 03/29/2004] [Accepted: 04/13/2004] [Indexed: 01/18/2023]
Abstract
The CARD domain protein BCL10 and paracaspase MALT1 are essential for the activation of IkappaB kinase (IKK) and NF-kappaB in response to T cell receptor (TCR) stimulation. Here we present evidence that TRAF6 ubiquitin ligase and TAK1 protein kinase mediate IKK activation by BCL10 and MALT1. RNAi-mediated silencing of MALT1, TAK1, TRAF6, and TRAF2 suppressed TCR-dependent IKK activation and interleukin-2 production in T cells. Furthermore, we have reconstituted the pathway from BCL10 to IKK activation in vitro with purified proteins of MALT1, TRAF6, TAK1, and ubiquitination enzymes including Ubc13/Uev1A. We find that a small fraction of BCL10 and MALT1 proteins form high molecular weight oligomers. Strikingly, only these oligomeric forms of BCL10 and MALT1 can activate IKK in vitro. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization, and activate the ligase activity of TRAF6 to polyubiquitinate NEMO. These results reveal an oligomerization --> ubiquitination --> phosphorylation cascade that culminates in NF-kappaB activation in T lymphocytes.
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Affiliation(s)
- Lijun Sun
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
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31
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Panwalkar A, Verstovsek S, Giles F. Nuclear factor-kappaB modulation as a therapeutic approach in hematologic malignancies. Cancer 2004; 100:1578-89. [PMID: 15073843 DOI: 10.1002/cncr.20182] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Nuclear factor-kappaB (NF-kappaB) is a collective term that refers to a small class of dimeric transcription factors for a number of genes, including growth factors, angiogenesis modulators, cell-adhesion molecules, and antiapoptotic factors. Although most NF-kappaB proteins promote transcription, some act as inactivating or repressive complexes. The most common p50-RelA (p65) dimer known "specifically" as NF-kappaB, is relatively abundant, controls the expression of numerous genes, and exists as an inactive cytoplasmic complex bound to inhibitory proteins of the NF-kappaB inhibitor (IkappaB) family. The inactive NF-kappaB-IkappaB complex is activated by a variety of stimuli, including proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. The release of NF-kappaB facilitates its translocation to the nucleus, where it promotes cell survival by initiating the transcription of genes encoding stress-response enzymes, cell-adhesion molecules, proinflammatory cytokines, and antiapoptotic proteins. Constitutive activation of NF-kappaB in the nucleus is observed in some hematologic disorders. With the recent approval of bortezomib for patients with advanced multiple myeloma, NF-kappaB modulation is likely to be a therapeutic endeavor of increasing interest in coming years.
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Affiliation(s)
- Amit Panwalkar
- Section of Developmental Therapeutics, Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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32
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Scharschmidt E, Wegener E, Heissmeyer V, Rao A, Krappmann D. Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappa B signaling. Mol Cell Biol 2004; 24:3860-73. [PMID: 15082780 PMCID: PMC387748 DOI: 10.1128/mcb.24.9.3860-3873.2004] [Citation(s) in RCA: 122] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2003] [Revised: 11/25/2003] [Accepted: 02/03/2004] [Indexed: 12/15/2022] Open
Abstract
Bcl10 is a critical regulator of NF-kappa B activity in T and B cells, coupling antigen receptor signaling to NF-kappa B activation via protein kinase C (PKC). Here we show that PKC or T-cell receptor (TCR)/CD28 signaling results in downregulation of Bcl10 protein levels, thereby attenuating NF-kappa B transcriptional activity. Bcl10 degradation requires an intact caspase recruitment domain and is not observed after stimulation with tumor necrosis factor alpha or lipopolysaccharides. Bcl10 downregulation is not affected by proteasome inhibitors but is accompanied by transient localization to lysosomal vesicles, suggesting involvement of the lysosomal pathway rather than the proteasome. The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation. Since CD3/CD28-induced activation of JNK is not affected by the decline of Bcl10, degradation of Bcl10 selectively terminates IKK/NF-kappa B signaling in response to TCR stimulation. Together, these results suggest a new mechanism of negative signaling in which TCR/PKC signaling initially activates Bcl10 but later promotes its degradation.
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33
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Galindo CL, Sha J, Ribardo DA, Fadl AA, Pillai L, Chopra AK. Identification of Aeromonas hydrophila cytotoxic enterotoxin-induced genes in macrophages using microarrays. J Biol Chem 2003; 278:40198-212. [PMID: 12824169 DOI: 10.1074/jbc.m305788200] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
A cytotoxic enterotoxin (Act) of Aeromonas hydrophila possesses several biological activities, and it induces an inflammatory response in the host. In this study, we used microarrays to gain a global and molecular view of the cellular transcriptional responses to Act and to identify important genes up-regulated by this toxin. Total RNA was isolated at 0, 2, and 12 h from Act-treated macrophages and applied to Affymetrix MGU74 arrays, and the data were processed using a multi-analysis approach to identify genes that might be critical in the inflammatory process evoked by Act. Seventy-six genes were significantly and consistently up-regulated. Many of these genes were immune-related, and several were transcription factors, adhesion molecules, and cytokines. Additionally, we identified several apoptosis-associated genes that were significantly up-regulated in Act-treated macrophages. Act-induced apoptosis of macrophages was confirmed by annexin V staining and DNA laddering. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay were used to verify increased expression of some inflammatory and apoptosis-associated genes identified by the microarray analysis. To further confirm Act-induced increases in gene expression, real-time RT-PCR was also used for selected genes. Taken together, the array data provided for the first time a global view of Act-mediated signal transduction and clearly demonstrated an inflammatory response and apoptosis mediated by this toxin in host cells at the molecular level.
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Affiliation(s)
- Cristi L Galindo
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1070, USA
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34
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Xue L, Morris SW, Orihuela C, Tuomanen E, Cui X, Wen R, Wang D. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nat Immunol 2003; 4:857-65. [PMID: 12910267 DOI: 10.1038/ni963] [Citation(s) in RCA: 160] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2003] [Accepted: 07/10/2003] [Indexed: 01/16/2023]
Abstract
Bcl10 is an intracellular protein essential for nuclear factor (NF)-kappaB activation after lymphocyte antigen receptor stimulation. Using knockout mice, we show that absence of Bcl10 impeded conversion from transitional type 2 to mature follicular B cells and caused substantial decreases in marginal zone and B1 B cells. Bcl10-deficient B cells showed no excessive apoptosis. However, both Bcl10-deficient follicular and marginal zone B cells failed to proliferate normally, although Bcl10-deficient marginal zone B cells uniquely failed to activate NF-kappaB efficiently after stimulation with lipopolysaccharide. Bcl10-deficient marginal zone B cells did not capture antigens, and Bcl10-deficient (Bcl10-/-) mice failed to initiate humoral responses, leading to an inability to clear blood-borne bacteria. Thus, Bcl10 is essential for the development of all mature B cell subsets.
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Affiliation(s)
- Liquan Xue
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
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35
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Park KJ, Choi SH, Choi DH, Park JM, Yie SW, Lee SY, Hwang SB. 1Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2. J Biol Chem 2003; 278:30711-8. [PMID: 12796506 DOI: 10.1074/jbc.m209623200] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) is a phosphoprotein possessing various functions. We have previously reported that the HCV NS5A protein interacts with tumor necrosis factor (TNF) receptor-associated factor (TRAF) domain of TRAF2 (Park, K.-J., Choi, S.-H., Lee, S. Y., Hwang, S. B., and Lai, M. M. C. (2002) J. Biol. Chem. 277, 13122-13128). Both TNF-alpha- and TRAF2-mediated nuclear factor-kappaB (NF-kappaB) activations were inhibited by NS5A-TRAF2 interaction. Because TRAF2 is required for the activation of both NF-kappaB and c-Jun N-terminal kinase (JNK), we investigated HCV NS5A protein for its potential capacity to modulate TRAF2-mediated JNK activity. Using in vitro kinase assay, we have found that NS5A protein synergistically activated both TNF-alpha- and TRAF2-mediated JNK in human embryonic kidney 293T cells. Furthermore, synergism of NS5A-mediated JNK activation was inhibited by dominant-negative form of MEK kinase 1. Our in vivo binding data show that NS5A does not inhibit interaction between TNF receptor-associated death domain and TRAF2 protein, indicating that NS5A and TRAF2 may form a ternary complex with TNF receptor-associated death domain. These results indicate that HCV NS5A protein modulates TNF signaling of the host cells and may play a role in HCV pathogenesis.
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Affiliation(s)
- Kyu-Jin Park
- Ilsong Institute of Life Science, Hallym University, Chuncheon 200-702, Korea
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36
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DeBiasi RL, Clarke P, Meintzer S, Jotte R, Kleinschmidt-Demasters BK, Johnson GL, Tyler KL. Reovirus-induced alteration in expression of apoptosis and DNA repair genes with potential roles in viral pathogenesis. J Virol 2003; 77:8934-47. [PMID: 12885910 PMCID: PMC167209 DOI: 10.1128/jvi.77.16.8934-8947.2003] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Reoviruses are a leading model for understanding cellular mechanisms of virus-induced apoptosis. Reoviruses induce apoptosis in multiple cell lines in vitro, and apoptosis plays a key role in virus-induced tissue injury of the heart and brain in vivo. The activation of transcription factors NF-kappaB and c-Jun are key events in reovirus-induced apoptosis, indicating that new gene expression is critical to this process. We used high-density oligonucleotide microarrays to analyze cellular transcriptional alterations in HEK293 cells after infection with reovirus strain T3A (i.e., apoptosis inducing) compared to infection with reovirus strain T1L (i.e., minimally apoptosis inducing) and uninfected cells. These strains also differ dramatically in their potential to induce apoptotic injury in hearts of infected mice in vivo-T3A is myocarditic, whereas T1L is not. Using high-throughput microarray analysis of over 12,000 genes, we identified differential expression of a defined subset of genes involved in apoptosis and DNA repair after reovirus infection. This provides the first comparative analysis of altered gene expression after infection with viruses of differing apoptotic phenotypes and provides insight into pathogenic mechanisms of virus-induced disease.
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Affiliation(s)
- Roberta L DeBiasi
- Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
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37
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Shimoke K, Kudo M, Ikeuchi T. MPTP-induced reactive oxygen species promote cell death through a gradual activation of caspase-3 without expression of GRP78/Bip as a preventive measure against ER stress in PC12 cells. Life Sci 2003; 73:581-93. [PMID: 12770613 DOI: 10.1016/s0024-3205(03)00351-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Glucose-regulated protein 78 (GRP78)/Immunoglobulin binding protein (Bip) is a chaperone which functions to protect cells from endoplasmic reticulum (ER) stress. GRP78/Bip is expressed following ER stress induced by thapsigargin, tunicamycin or chemical factors. However, the mechanism of progression of ER stress against stress factors is still obscure. We examined whether reactive oxygen species (ROS) were involved in GRP78/Bip expression and caspase-3 activity was induced in PC12 cells using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce ROS. We report that PC12 cells lost viability in the presence of MPTP for 24 hours as a partial effect of ROS. We also show that N-acetyl-L-cysteine diminished the MPTP-induced apoptosis with expunction of ROS. Furthermore, we observed that GRP78/Bip was not up-regulated and the caspase-3 activity was increased in the presence of MPTP. These results suggest that insubstantial ROS do not contribute to the ER stress-mediated cell death while caspase-3 is involved in ROS-promoted cell death in MPTP-treated cells.
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Affiliation(s)
- Koji Shimoke
- Laboratory of Neurobiology, Faculty of Engineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan. /jp
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38
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Abstract
TNF-receptor-associated factors (TRAFs) are the bottleneck of the TNF-receptor (TNF-R) family signal transduction. They integrate the signalling from many members of the TNF-R family and initiate intracellular signalling cascades aimed at the activation of NF-kappaB and c-jun, the reprogramming of gene expression and the control of cell death. Deregulation of these pathways is the cause of several autoimmune and inflammatory diseases. The specificity and interaction of the members of the TRAF family with the TNF-R entails the recognition of just a 4 - 6 amino acid motif in the cytosolic region of the receptor, suitable as an attractive target for drug discovery. This review summarises the current knowledge on TRAFs and discusses the pros and cons of their application as targets for drug discovery.
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Affiliation(s)
- Juan M Zapata
- The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
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39
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Shinoda S, Skradski SL, Araki T, Schindler CK, Meller R, Lan JQ, Taki W, Simon RP, Henshall DC. Formation of a tumour necrosis factor receptor 1 molecular scaffolding complex and activation of apoptosis signal-regulating kinase 1 during seizure-induced neuronal death. Eur J Neurosci 2003; 17:2065-76. [PMID: 12786973 DOI: 10.1046/j.1460-9568.2003.02655.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The consequences of activation of tumour necrosis factor receptor 1 (TNFR1) during neuronal injury remain controversial. The apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase, can mediate cell death downstream of TNFR1. Presently, we examined the formation of the TNFR1 signalling cascade and response of ASK1 during seizure-induced neuronal death. Brief (40 min) seizures were induced in rats by intra-amygdala microinjection of kainic acid, which elicited unilateral hippocampal CA3 neuronal death. Seizures caused a rapid decline in the expression of the silencer of death domains protein within injured CA3. Co-immunoprecipitation analysis revealed a commensurate assembly of a TNFR1 scaffold complex containing TNFR-associated death domain protein, receptor interacting protein and TNFR-activating factor 2. In addition, recruitment of TNFR-activating factor 2 was likely promoted by Bcl10-mediated sequestering of cellular inhibitor of apoptosis protein 2. Apoptosis signal-regulating kinase 1 was sequestered in a complex that contained the molecular chaperone 14-3-3beta and protein phosphatase 5. Seizures triggered its dissociation, and the phosphorylation of the ASK1 substrates, mitogen-activated protein kinase kinase 3/6 and 4. Subsequently, protein phosphatase 5 translocated into the nuclei of degenerating CA3 neurons, while ASK1 colocalized with the adaptor proteins Daxx and TNFR-activating factor 2 at the outer membrane of injured CA3 neurons. Neutralizing antibodies to TNFalpha reduced the numbers of DNA damaged cells within the injured hippocampus. These data suggest ASK1 may be involved in the mechanism of seizure-induced neuronal death downstream of a TNFR1 death-signalling complex.
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Affiliation(s)
- Sachiko Shinoda
- Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon, USA
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40
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Müller-Hermelink HK. Genetic and molecular genetic studies in the diagnosis of B-cell lymphomas: marginal zone lymphomas. Hum Pathol 2003; 34:336-40. [PMID: 12733112 DOI: 10.1053/hupa.2003.98] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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41
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Abstract
The development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma depends critically on Helicobacter pylori infection. The bacterial infection stimulates the lymphoma B-cells through both direct (auto-antigen) and indirect (H. pylori specific intra-tumour T-cells) immunological stimulation. It also promotes the acquisition of genetic abnormality through activated neutrophils, which release oxygen reactive species. Malignant clones bearing t(11;18)(q21;q21) form lymphomas that are H. pylori growth independent. Those without t(11;18)(q21;q21) but with other genetic abnormality such as trisomy 3 depend critically on H. pylori mediated immune response at early stages and are therefore responsive to H. pylori eradication. However, at late stages when additional genetic defects such as t(1;14)(p22;q32) accumulate, the tumour may escape its growth dependence on H. pylori mediated immune response. Detection of these chromosomal translocations has significant implication in clinical management of patients with gastric MALT lymphoma.
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Affiliation(s)
- Ming-Qing Du
- Department of Histopathology, Royal Free and University College Medical School, University of College London, London, UK.
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42
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Gaide O, Favier B, Legler DF, Bonnet D, Brissoni B, Valitutti S, Bron C, Tschopp J, Thome M. CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation. Nat Immunol 2002; 3:836-43. [PMID: 12154360 DOI: 10.1038/ni830] [Citation(s) in RCA: 275] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
CARMA1 is a lymphocyte-specific member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, which coordinate signaling pathways emanating from the plasma membrane. CARMA1 interacts with Bcl10 via its caspase-recruitment domain (CARD). Here we investigated the role of CARMA1 in T cell activation and found that T cell receptor (TCR) stimulation induced a physical association of CARMA1 with the TCR and Bcl10. We found that CARMA1 was constitutively associated with lipid rafts, whereas cytoplasmic Bcl10 translocated into lipid rafts upon TCR engagement. A CARMA1 mutant, defective for Bcl10 binding, had a dominant-negative (DN) effect on TCR-induced NF-kappa B activation and IL-2 production and on the c-Jun NH(2)-terminal kinase (Jnk) pathway when the TCR was coengaged with CD28. Together, our data show that CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation and CD28 costimulation-dependent Jnk activation.
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Affiliation(s)
- Olivier Gaide
- Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland
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43
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Cheng H, Cenciarelli C, Tao M, Parks WP, Cheng-Mayer C. HTLV-1 Tax-associated hTid-1, a human DnaJ protein, is a repressor of Ikappa B kinase beta subunit. J Biol Chem 2002; 277:20605-10. [PMID: 11927590 DOI: 10.1074/jbc.m201204200] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
hTid-1, a human DnaJ protein, is a novel cellular target for HTLV-1 Tax. Here, we show that hTid-1 represses NF-kappaB activity induced by Tax as well as other activators such as tumor necrosis factor alpha (TNFalpha) and Bcl10. hTid-1 specifically suppresses serine phosphorylation of IkappaBalpha by activated IkappaB kinase beta (IKKbeta), but the activities of other serine kinases including p38, ERK2, and JNK1 are not affected. The suppressive activity of hTid-1 on IKKbeta requires a functional J domain that mediates association with heat shock proteins and results in prolonging the half-life of the NF-kappaB inhibitors IkappaBalpha and IkappaBbeta. Collectively, our data suggest that hTid-1, in association with heat shock proteins, exerts a negative regulatory effect on the NF-kappaB activity induced by various extracellular and intracellular activators including HTLV-1 Tax.
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Affiliation(s)
- Hua Cheng
- Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York 10021, USA.
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44
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Kawasaki C, Ohshima K, Muta H, Muta K, Deyev V, Podack ER, Kikuchi M. Prognostic value of Bcl 10 rearrangement in diffuse large B-cell lymphoma. Leuk Lymphoma 2002; 43:823-6. [PMID: 12153171 DOI: 10.1080/10428190290016953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
The role of bcl 10, a recently cloned apoptosis-associated gene, in diffuse large B-cell lymphoma (DLBL) is unknown. Here we determined the role of bcl 10 gene rearrangement on prognosis. Bcl 10 rearrangement was examined by Southern blot. Bcl 10 rearrangement was detected in 20 of 137 (14.6%) samples of DLBL. The frequency of bcl 10 rearrangement was higher in extranodal (eight of 38 cases, 21%) than in nodal (12 of 99, 12%) DLBL. The survival rate in patients with bcl 10 rearrangement tended to be better than in those with germ-line bcl 10, albeit statistically insignificant probably due to the small population sample. The superior prognosis in patients with bcl 10 rearrangement might be due to bcl 10-induced enhanced apoptosis.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Child
- Chromosomes, Human, Pair 1
- Chromosomes, Human, Pair 14
- Gene Rearrangement
- Humans
- Lymphoma, B-Cell/genetics
- Lymphoma, B-Cell/mortality
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/mortality
- Middle Aged
- Prognosis
- Proto-Oncogenes
- Survival Rate
- Translocation, Genetic
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Affiliation(s)
- C Kawasaki
- First Department of Pathology, School of Medicine, Fukuoka University, Japan
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45
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Abstract
The transcription factor NFkappaB is activated by numerous stimuli. Once NFkappaB is fully activated, it participates in the regulation of various target genes in different cells to exert its biological functions. NFkappaB has often been referred to as a central mediator of the immune response, since a large variety of bacteria and viruses can lead to the activation of NFkappaB, which in turn controls the expression of many inflammatory cytokines, chemokines, immune receptors, and cell surface adhesion molecules. Recent studies have shown that NFkappaB may function more generally as a central regulator of stress responses, since different stressful conditions, including physical stress, oxidative stress, and exposure to certain chemicals, also lead to NFkappaB activation. Furthermore, NFkappaB blocks cell apoptosis in several cell types. Taken together, these findings make it clear that NFkappaB plays an important role in cell proliferation and differentiation. It is the intention of this review to cover the various NFkappaB-dependent signaling pathways, thereby to achieve a better understanding of the mechanisms of NFkappaB activation and the physiological functions of activated NFkappaB.
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Affiliation(s)
- Xiaoxia Li
- Department of Immunology/NB30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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46
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Abstract
The development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is dependent on Helicobacter pylori infection. Bacterial colonisation of the gastric mucosa triggers lymphoid infiltration and the formation of acquired MALT. The bacterial infection induces and sustains an actively proliferating B-cell population through direct (autoantigen) and indirect (intratumoral T cells specific for H. pylori) immunological stimulation. Moreover, the bacterial infection provokes a neutrophilic response, which causes the release of oxygen free radicals. These reactive species may promote the acquisition of genetic abnormalities and malignant transformation of reactive B cells. A transformed clone carrying the translocation t(1;18)(q21;q21) forms a MALT lymphoma, the growth of which is independent of H. pylori and will not respond to bacterial eradication. Malignant clones without t(11;18)(q21;q21), but with other genetic abnormalities, such as trisomy 3 or microsatellite instability, depend critically on immune stimulation mediated by H. pylori for their clonal expansion. In the early stages, the tumour can be successfully treated by eradication of the bacterium, whereas at later stages the tumour may escape its growth dependency through acquisition of additional genetic abnormalities such as t(1;14)(p22;q32) and t(1;2)(p22,p12) involving the BCL-10 gene. Finally, further genetic abnormalities, such as inactivation of the tumour suppressor genes, p53 and p16, can lead to high-grade transformation. Detection of these abnormalities may help with the clinical management of patients with gastric MALT lymphoma.
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Affiliation(s)
- Ming-Qing Du
- Department of Histopathology, Royal Free and University College Medical School, University College London, UK.
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47
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Abstract
Malignant transformation of B cells can occur at various steps of lymphocyte development, starting from early B-cell progenitors up to mature B cells, which reflects the heterogeneity of B-cell malignancies with regard to their biologic and clinical behavior. The genetic characterization of B-cell neoplasms during the past two decades has elucidated the mechanisms underlying B-cell lymphomagenesis and led to a more precise definition of lymphoma subgroups. This progress is reflected in the upcoming World Health Organization classification for hematologic neoplasms, which stresses the diagnostic importance of recurrent genetic alterations in leukemias and lymphomas. In the recent past, several genes deregulated by such recurrent chromosomal aberrations have been identified. In addition, the recent introduction of microarray technology has now allowed a more global assessment of gene dysregulation in B-cell oncogenesis and provided a new means for more exactly defining the molecular hallmarks of distinct lymphoma subtypes. This review will focus on recently described molecular features of B-cell lymphomas discovered by the application of new molecular cytogenetic techniques, advanced breakpoint cloning strategies, and microarray approaches.
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Affiliation(s)
- R Siebert
- Institute of Human Genetics, University Hospital Kiel, Christian-Albrechts University Kiel, Kiel, Germany
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48
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Liu H, Ye H, Dogan A, Ranaldi R, Hamoudi RA, Bearzi I, Isaacson PG, Du MQ. T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood 2001; 98:1182-7. [PMID: 11493468 DOI: 10.1182/blood.v98.4.1182] [Citation(s) in RCA: 190] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a multistep process and can be clinico-pathologically divided into Helicobacter pylori-associated gastritis, low-grade tumors, and high-grade tumors. The molecular events underlying this progression are largely unknown. However, identification of the genes involved in MALT lymphoma-specific t(11;18)(q21;q21) and t(1;14)(p22;q32) has provided fresh insights into the pathogenesis of this disease. T(11;18)(q21;q21) results in a chimeric transcript between the API2 and the MALT1 genes, whereas t(1;14) (p22;q32) causes aberrant nuclear BCL10 expression. Significantly, nuclear BCL10 expression also occurs frequently in MALT lymphomas without t(1;14)(p22;q32), suggesting an important role for BCL10 in lymphoma development. Thirty-three cases of H pylori gastritis, 72 MALT lymphomas, and 11 mucosal diffuse large B-cell lymphomas (DLBCL) were screened for t(11;18)(q21;q21) by reverse transcription-polymerase chain reaction followed by sequencing. BCL10 expression in lymphoma cases was examined by immunohistochemistry. The API2--MALT1 fusion transcript was not detected in H pylori gastritis and mucosal DLBCL but was found in 25 of 72 (35%) MALT lymphomas of various sites. Nuclear BCL10 expression was seen in 28 of 53 (53%) of MALT lymphomas. Of the gastric cases, the largest group studied, the frequency of both t(11;18)(q21;q21) and nuclear BCL10 expression was significantly higher in tumors that showed dissemination to local lymph nodes or distal sites (14 of 18 = 78% and 14 of 15 = 93%, respectively) than those confined to the stomach (3 of 29 = 10% and 10 of 26 = 38%). Furthermore, t(11;18)(q21;q21) closely correlated with BCL10 nuclear expression. These results indicate that both t(11;18)(q21;q21) and BCL10 nuclear expression are associated with advanced MALT lymphoma and that their oncogenic activities may be related to each other. (Blood. 2001;98:1182-1187)
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MESH Headings
- Adaptor Proteins, Signal Transducing
- Adult
- Aged
- B-Cell CLL-Lymphoma 10 Protein
- Biomarkers/analysis
- Chromosome Aberrations/pathology
- Chromosome Disorders
- Chromosomes, Human, Pair 11/genetics
- Chromosomes, Human, Pair 18/genetics
- Disease Progression
- Female
- Humans
- Lymphoma, B-Cell, Marginal Zone/etiology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/metabolism
- Male
- Middle Aged
- Neoplasm Proteins/metabolism
- Nuclear Proteins/metabolism
- Oncogene Proteins, Fusion/genetics
- RNA, Messenger/analysis
- Stomach Neoplasms/etiology
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Translocation, Genetic/genetics
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Affiliation(s)
- H Liu
- Department of Histopathology, Royal Free and University College Medical School, London, United Kingdom
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Yui D, Yoneda T, Oono K, Katayama T, Imaizumi K, Tohyama M. Interchangeable binding of Bcl10 to TRAF2 and cIAPs regulates apoptosis signaling. Oncogene 2001; 20:4317-23. [PMID: 11466612 DOI: 10.1038/sj.onc.1204576] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2001] [Revised: 03/09/2001] [Accepted: 04/30/2001] [Indexed: 11/09/2022]
Abstract
Bcl10 was identified as a candidate gene responsible for low grade B cell lymphomas of mucosa-associated lymphoid tissue. Overexpression of Bcl10 in cultured cells was reported to promote apoptosis, however, the mechanism of regulation of apoptosis mediated by Bcl10 has not been demonstrated. In the present study, we analysed the apoptosis signaling pathway mediated by Bcl10, focusing on phosphorylation of Bcl10 and the dynamic interaction with its binding partners during apoptosis. Previously, we have demonstrated that Bcl10 potentially interacts with the other apoptosis regulator, TNF receptor associated factor-2 (TRAF2) and inhibitor of apoptosis proteins (cIAPs). The present results showed that the complex formation of these molecules was regulated by phosphorylation of Bcl10, that is, phosphorylation of Bcl10 resulted in binding of Bcl10 to cIAPs and the dissociation of it from TRAF2. Moreover, hyperphosphorylation of Bcl10 enhanced apoptosis, suggesting that changes in the binding partners of Bcl10 were correlated to the promotion of apoptosis as mediated by Bcl10. Indeed, the mutant which was deleted from the binding site of Bcl10 for cIAPs, could not induce apoptosis. These findings indicate that Bcl10 is a mediator of apoptosis signaling, by switching over binding to cIAPs from TRAF2 through the events of Bcl10 phosphorylation.
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Affiliation(s)
- D Yui
- Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University. 2-2 Yamadaoka Suita, Osaka 565-0871, Japan.
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Müllauer L, Gruber P, Sebinger D, Buch J, Wohlfart S, Chott A. Mutations in apoptosis genes: a pathogenetic factor for human disease. Mutat Res 2001; 488:211-31. [PMID: 11397650 DOI: 10.1016/s1383-5742(01)00057-6] [Citation(s) in RCA: 94] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Cell death by apoptosis is exerted by the coordinated action of many different gene products. Mutations in some of them, acting at different levels in the apoptosis process, have been identified as cause or contributing factor for human diseases. Defects in the transmembrane tumor necrosis factor receptor 1 (TNF-R1) lead to the development of familial periodic fever syndromes. Mutations in the homologous receptor Fas (also named CD95; Apo-1) are observed in malignant lymphomas, solid tumors and the autoimmune lymphoproliferative syndrome type I (ALPS I). A mutation in the ligand for Fas (Fas ligand; CD95 ligand, Apo-1 ligand), which induces apoptosis upon binding to Fas, was described in a patient with systemic lupus erythematodes and lymphadenopathy. Perforin, an other cytotoxic protein employed by T- and NK-cells for target cell killing, is mutated in chromosome 10 linked cases of familial hemophagocytic lymphohistiocytosis. Caspase 10, a representative of the caspase family of proteases, which plays a central role in the execution of apoptosis, is defect in autoimmune lymphoproliferative syndrome type II (ALPS II). The intracellular pro-apoptotic molecule bcl-10 is frequently mutated in mucosa-associated lymphoid tissue (MALT) lymphomas and various non-hematologic malignancies. The p53, an executioner of DNA damage triggered apoptosis, and Bax, a pro-apoptotic molecule with the ability to perturb mitochondrial membrane integrity, are frequently mutated in malignant neoplasms. Anti-apoptotic proteins like bcl-2, cellular-inhibitor of apoptosis protein 2 (c-IAP2) and neuronal apoptosis inhibitory protein 1 (NAIP1) are often altered in follicular lymphomas, MALT lymphomas and spinal muscular atrophy (SMA), respectively. This article reviews the current knowledge on mutations of apoptosis genes involved in the pathogenesis of human diseases and summarises the gradual transformation of discoveries in apoptosis research into benefits for the clinical management of diseases.
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Affiliation(s)
- L Müllauer
- Institute of Clinical Pathology, University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria.
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