Transglutaminase 2 Induces Nuclear Factor-κB Activation via a Novel Pathway in BV-2 Microglia

Lee, Jongmin; Kim, Yoon-Seong; Choi, Dong‐Hee; Bang, Moon Suk; Han, Tai Ryoon; Joh, Tong H.; Kim, Soo-Youl

doi:10.1074/jbc.m407627200

Cited by 195 publications

(196 citation statements)

References 75 publications

(75 reference statements)

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“…breast cancer cells and NCI/ADR-RES drug-resistant ovarian cancer cells) or no expression of TGase 2 (MCF7 breast cancer cells) and human embryonic kidney cell line 293 (HEK293) immortalized kidney cells). The results of several recent studies from our laboratory have shown that increased TGase 2 expression has a key role in the acquisition of drug resistance by cancer cells (Lee et al, 2004;Herman et al, 2006;Kim et al, 2006Kim et al, , 2008Park et al, 2006). The level of VHL in NCI/ADR-RES and MDA-MB-231 breast cancer cells was lower than in HEK-293 and MCF7 cells, and the level of endogenous VHL inversely correlated with TGase 2 in the cancer cell lines (Figure 1c).…”

Section: Inverse Correlation Between Vhl and Tgasementioning

confidence: 77%

“…A series of studies have shown that the induction of TGase 2 contributes to constitutive nuclear factor-kB (NF-kB) activation via polymerization of the inhibitor of NF-kB (Lee et al, 2004;Kim et al, 2006;Park et al, 2006), and that this is one of the mechanisms of drug resistance in cancer cells (Mehta et al, 2004;Herman et al, 2006;Kim et al, 2006Kim et al, , 2008Kim et al, , 2009Park et al, 2006;Gangadharan et al, 2009). Increased TGase 2 expression correlates with increased NF-kB activity in breast cancer tissue ).…”

Section: Introductionmentioning

confidence: 99%

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Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking

et al. 2011

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Section: Inverse Correlation Between Vhl and Tgasementioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking

et al. 2011

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“…1), suggesting that TGase 2 is involved in the development of doxorubicin resistance independently of EGF signaling. It has been shown that TGase 2 can be induced by EGF (3,27). However, TGase 2 can also be activated or induced by a variety of chemical, physical, and biological stimuli (23).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been shown that inhibition of NF-nB enhances the sensitivity of tumor cells to apoptosis induced by chemotherapeutic agents (26). TGase 2 expression can be induced by EGF (3,27). Therefore, in the current study, we examined several different breast cancer cell lines, representing EGF receptor (EGFR)-positive and EGFR-negative breast cancers, to determine the role of TGase 2-mediated NF-nB activation in drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

et al. 2006

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Induction of transglutaminase 2 (TGase 2) by epidermal growth factor (EGF) in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of TGase 2 in the development of these tumor-related phenotypes remains to be elucidated, but it has been shown that expression of a dominant-negative form of TGase 2 reverses EGF-mediated chemoresistance in breast cancer cells. We examined several different breast cancer cell lines, representing both EGF receptor (EGFR)-positive and EGFR-negative breast cancers, and found that doxorubicin-resistant cells had a higher level of TGase 2 compared with doxorubicin-sensitive cells independent of the EGFR expression level. TGase 2 inhibition increased the chemosensitivity of drug-resistant cells, concomitant with a decrease in nuclear factor-KB (NF-KB) activity. Increasing the level of TGase 2 in drugsensitive cells by transient transfection reduced the level of inhibitory subunit A of NF-KB (IKBA) and increased NF-KB activity in these cells. Inhibition of TGase 2 in drug-resistant cells by RNA interference increased the levels of IKBA, and this correlated with a shift in the accumulation of NF-KB from the nucleus to the cytosol. We recently showed that TGase 2 activated NF-KB through polymerization and depletion of free IKBA during inflammation. Therefore, increased expression of TGase 2 and subsequent activation of NF-KB may contribute to drug resistance in breast cancer cells independently of EGF signaling. (Cancer Res 2006; 66(22): 10936-43)

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“…Although tTG is a multifunctional enzyme, it seems that its prevalent role in the inflammatory reaction is linked to stabilization of the extracellular matrix increasing the resistance to mechanical and proteolytic degradation. It has been shown that tTG is overexpressed in rheumatoid lesions [27] and increased tTG activity induces inflammation via NF-kB activation without I-kBa kinase signaling [28]. Taken together, these reports suggest that tTG plays a crucial role in the pathogenesis of inflammatory diseases such as RA.…”

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confidence: 88%

Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

Dzhambazov

Lindh

Engström³

et al. 2009

Eur J Immunol

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The calcium-dependent enzyme tissue transglutaminase (tTG) is associated with diverse biological functions, such as induction of apoptosis, modeling of the extracellular matrix, receptor-mediated endocytosis, cell growth and differentiation, cell adhesion and signal transduction. Also, it may deamidate glutamine residues to glutamic acid and catalyze cross-linking of proteins. In this study, we have investigated the impact of tTG for posttranslational modifications and cross-linking of the immunodominant T-cell epitope CII260-270 and their effects on the collagen-induced arthritis, an animal model for rheumatoid arthritis. By using mass spectrometry analysis and hybridoma assays, we have demonstrated that tTG could perform both types of modifications (deamidation and cross-link formation) on the immunodominant T-cell epitope CII259-273. Replacement of the glutamine at position 267 with glutamic acid leads to a decreased binding affinity to MHC II. T cells recognized both non-modfied (Q 267 ) and modified (E 267 ) CII259-273-peptides. We also show that administration of tTG leads to increased incidence, severity and histopathological manifestations of collagen-induced arthritis in mice. Moreover, we conclude that both processes, deamidation and cross-linking, are involved in the tTG-catalyzed reactions, and in vivo administration of tTG enhances arthritis severity and joint destruction in mice.Key words: Collagen-induced arthritis . CII-peptide . Posttranslational modifications .T cells . Tissue transglutaminase IntroductionPosttranslational modifications of proteins are being recognized as increasingly important for the initiation and pathogenesis of autoimmune diseases. Such modifications could lead to breaking of the immunological tolerance to self proteins by creation of new epitopes within the target antigen. Rheumatoid arthritis (RA) is an autoimmune disease involving an inflammatory attack on peripheral cartilaginous joints characterized by leukocyte infiltration, secretion of inflammatory cytokines and auto-Ab, and subsequent cartilage destruction, irreversible bone erosion and joint deformation. Major candidate autoantigens in RA that are locally expressed in the joint are type II collagen (CII), fibrin, and proteoglycans. CII is of particular interest, since T-and B-cell autoimmune responses to this protein leads to collagen-induced arthritis (CIA) in mice [1], rats [2] and primates [3,4], which shares many phenotypic features with RA. The shared immunodominant T-cell epitope in CIA and RA has been identified as . Amino acids of this immunodominant core can be posttranslationally modified either by enzymatic processes or spontaneously. It is well established that during aging, inflammation, trauma or other pathologic processes, the frequency of posttranslational modifications, such as glycosylation, glycation, citrullination, oxidation, deamidation/transamidation or 2412phosphorylation, is increased [10,11]. The role of glycosylated immunodominant CII260-270-peptide for development of autoimmune arthri...

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Transglutaminase 2 Induces Nuclear Factor-κB Activation via a Novel Pathway in BV-2 Microglia

Cited by 195 publications

References 75 publications

Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking

Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

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