Transglutaminase 2: A New Paradigm for NF‐κB Involvement in Disease

Kim, Soo-Youl

doi:10.1002/9781118105771.ch4

Cited by 17 publications

(7 citation statements)

References 155 publications

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“…How TG2 mediates IκBα degradation is not yet known but is independent of the proteasomal pathway [31]. An earlier study by Kim [34] suggested that TG2-catalyzed polymerization of IκBα results in its degradation and activation of NF-κB. However, our own studies demonstrated that catalytically active (wild-type) or inactive mutants (C277S and W241A) of TG2 were equally effective in mediating the degradation of IκBα and inducing NF-κB activation in mammary epithelial cells [31].…”

Section: Tg2-regulated Signaling Pathwaysmentioning

confidence: 99%

Tissue transglutaminase as a central mediator in inflammation-induced progression of breast cancer

2013

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TGM2 is a stress-responsive gene that encodes a multifunctional and structurally complex protein called tissue transglutaminase (abbreviated as TG2 or tTG). TGM2 expression is frequently upregulated during inflammation and wounding. Emerging evidence indicates that TGM2 expression is aberrantly upregulated in multiple cancer cell types, particularly those selected for resistance to chemotherapy and radiation therapy and those isolated from metastatic sites. It is becoming increasingly evident that chronic expression of TG2 in epithelial cancer cells initiates a complex series of signaling networks which contributes to the development of drug resistance and an invasive phenotype. For example, forced or basal high expression of TG2 in mammary epithelial cells is associated with activation of nuclear transcription factor-kappa B (NF-κB), Akt, focal adhesion kinase, and hypoxia-inducible factor. All of these changes are considered hallmarks of aggressive tumors. TG2 expression is able to induce the developmentally regulated program of epithelial-to-mesenchymal transition (EMT) and to confer cancer stem cell (CSC) traits in mammary epithelial cells; both EMT and CSCs have been implicated in cancer metastasis and resistance to standard therapies. Importantly, TG2 expression in tumor samples is associated with poor disease outcome, increased drug resistance, and increased incidence of metastasis. These observations imply that TG2 plays a crucial role in promoting an aggressive phenotype in mammary epithelial cells. In this review, we discuss recent evidence that TG2-regulated pathways contribute to the aggressive phenotype in breast cancer.

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Section: Tg2-regulated Signaling Pathwaysmentioning

confidence: 99%

Tissue transglutaminase as a central mediator in inflammation-induced progression of breast cancer

2013

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“…In addition, TGase 2 plays important roles in fibroblast function [ 7 ], wound healing [ 8 ], macrophage phagocytosis [ 9 ], in the development of cancers [ 10 , 11 , 12 ], and neurological disorders such as Huntington’s and Alzheimer’s diseases [ 13 , 14 , 15 ]. Other biological functions of TGase 2 have been discussed in reviews [ 16 , 17 ]; these include nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation through inhibition of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (I-κBα) [ 18 ], hypoxia-inducible factor 1-α (HIF-1α) activation through inhibition of von Hippel-Lindau tumor suppressor (VHL) [ 19 ], and suppression of cancer cell apoptosis through inhibition of p53 [ 5 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition

Lee

Kim

et al. 2018

Cancers

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In general, expression of transglutaminase 2 (TGase 2) is upregulated in renal cell carcinoma (RCC), resulting in p53 instability. Previous studies show that TGase 2 binds to p53 and transports it to the autophagosome. Knockdown or inhibition of TGase 2 in RCC induces p53-mediated apoptosis. Here, we screened a chemical library for TGase 2 inhibitors and identified streptonigrin as a potential therapeutic compound for RCC. Surface plasmon resonance and mass spectroscopy were used to measure streptonigrin binding to TGase 2. Mass spectrometry analysis revealed that streptonigrin binds to the N-terminus of TGase 2 (amino acids 95–116), which is associated with inhibition of TGase 2 activity in vitro and with p53 stabilization in RCC. The anti-cancer effects of streptonigrin on RCC cell lines were demonstrated in cell proliferation and cell death assays. In addition, a single dose of streptonigrin (0.2 mg/kg) showed marked anti-tumor effects in a preclinical RCC model by stabilizing p53. Inhibition of TGase 2 using streptonigrin increased p53 stability, which resulted in p53-mediated apoptosis of RCC. Thus, targeting TGase 2 may be a new therapeutic approach to RCC.

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“…Transglutaminase 2 is responsible for the change of normal physiology including fibroblast function [4], wound healing [5], clearance of apoptotic cells [6], macrophage phagocytosis [7], glucose tolerance [8] as well as playing a key role in the development of disease pathogenesis including various cancers [9,10,11], and several neurological disorders including Huntington’s, Alzheimer’s and Parkinson’s [12,13,14]. More reactions and biological functions of TGase 2 are discussed in the reviews [1,15] including nuclear factor κB (NF-κB) activation through NF-κB inhibitor α (I-κBα) inhibition [16], hypoxia-inducible factor 1α (HIF-1α) activation through von Hippel–Lindau tumor suppressor (VHL) inhibition [17] and suppression of apoptosis in cancer through p53 inhibition [15,18].…”

Section: Introductionmentioning

confidence: 99%

New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds

Kim

2018

Medical Sciences

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Transglutaminase 2 (EC 2.3.2.13; TG2 or TGase 2) plays important roles in the pathogenesis of many diseases, including cancers, neurodegeneration, and inflammatory disorders. Under normal conditions, however, mice lacking TGase 2 exhibit no obvious abnormal phenotype. TGase 2 expression is induced by chemical, physical, and viral stresses through tissue-protective signaling pathways. After stress dissipates, expression is normalized by feedback mechanisms. Dysregulation of TGase 2 expression under pathologic conditions, however, can potentiate pathogenesis and aggravate disease severity. Consistent with this, TGase 2 knockout mice exhibit reversal of disease phenotypes in neurodegenerative and chronic inflammatory disease models. Accordingly, TGase 2 is considered to be a potential therapeutic target. Based on structure–activity relationship assays performed over the past few decades, TGase 2 inhibitors have been developed that target the enzyme’s active site, but clinically applicable inhibitors are not yet available. The recently described the small molecule GK921, which lacks a group that can react with the active site of TGase 2, and efficiently inhibits the enzyme’s activity. Mechanistic studies revealed that GK921 binds at an allosteric binding site in the N-terminus of TGase 2 (amino acids (a.a.) 81–116), triggering a conformational change that inactivates the enzyme. Because the binding site of GK921 overlaps with the p53-binding site of TGase 2, the drug induces apoptosis in renal cell carcinoma by stabilizing p53. In this review, we discuss the possibility of developing TGase 2 inhibitors that target the allosteric binding site of TGase 2.

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Transglutaminase 2: A New Paradigm for NF‐κB Involvement in Disease

Cited by 17 publications

References 155 publications

Tissue transglutaminase as a central mediator in inflammation-induced progression of breast cancer

Tissue transglutaminase as a central mediator in inflammation-induced progression of breast cancer

Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition

New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds

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