Two isoforms of tissue transglutaminase mediate opposing cellular fates

Antonyak, Marc A.; Jansen, Jaclyn M.; Miller, Allison M.; Ly, Thi; Endo, Makoto; Cerione, Richard A.

doi:10.1073/pnas.0604844103

Cited by 97 publications

(112 citation statements)

References 32 publications

(51 reference statements)

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…Transglutaminase 2 has been implicated to be a participant in apoptotic process (Antonyak et al, 2006;Yamaguchi and Wang, 2006;Verma and Mehta, 2007 (Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

“…It was previously reported that NF-kB signal pathway is activated by hypoxic stress (Antonyak et al, 2006), and TG2 is involved in the activation of NF-kB signaling (Park et al, 2006). We examined the activation of NFkB signal pathway using reporter constructs containing NF-kB responsible elements (3kB-Luc, and cellular inhibitor of apoptosis 2 luciferase (cIAP2-Luc)).…”

Section: Activation Of Nuclear Factor (Nf)-kb Pathway By Transglutamimentioning

confidence: 99%

See 1 more Smart Citation

Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-κB activity in hypoxic tumor cells

et al. 2009

View full text Add to dashboard Cite

The expression of hypoxia-inducible factor-1 (HIF-1) correlates with poor clinical outcomes and confers resistance to the apoptosis of the tumor cells that are exposed to hypoxia. Presently, the mechanism underlying this phenomenon is poorly understood. In this study we provide evidence that transglutaminase 2 (TG2), an enzyme that catalyses protein crosslinking reactions, is a transcriptional target of HIF-1 to enhance the survival of hypoxic cells. We found that hypoxia induces TG2 expression through an HIF-1 dependent pathway and concurrently activates intracellular TG2. The hypoxic cells overexpressing TG2 showed resistance to apoptosis. Conversely, the hypoxic cells treated with either TG2 inhibitor or small interfering RNA (siRNA) became sensitive to apoptosis. Activation of TG2 in response to hypoxic stress inhibited caspase-3 activity by forming crosslinked multimer, resulting in insoluble aggregates. TG2 also activates nuclear factor (NF)-jB pathway after hypoxic stress, and thereby induces the expression of cellular inhibitor of apoptosis 2. The anti-apoptotic role of TG2 was further confirmed in vivo using xenografts in athymic mice. Our results indicate that TG2 is an antiapoptotic mediator of HIF-1 through modulating both apoptosis and survival pathways and may confer a selective growth advantage to tumor cells. These findings suggest that the inhibition of TG2 may offer a novel strategy for anticancer therapy.

show abstract

“…Transglutaminase 2 has been implicated to be a participant in apoptotic process (Antonyak et al, 2006;Yamaguchi and Wang, 2006;Verma and Mehta, 2007 (Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

Section: Activation Of Nuclear Factor (Nf)-kb Pathway By Transglutamimentioning

confidence: 99%

Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-κB activity in hypoxic tumor cells

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Figure 2A shows the Coomassie blue-stained SDS gel profile for wild-type TGase-2 and some representative examples of the mutants used in this study. Unlike the case for the TGase-S protein (28), none of the TGase-2 point-mutants showed detectable aggregation during their purification (data not shown). We then examined their GTP-binding capability by using a spectroscopic assay that takes advantage of the fluorescence properties of the GTP-analog, BODIPY-FL GTPγS (BOD-GTPγS).…”

Section: Generation Of Gtp-binding-defective Mutants Of Human Tgase-2mentioning

confidence: 99%

“…Recently, we have found that one possible explanation for these apparent discrepancies may arise from the alternative processing of the TGase-2 transcript (28). In fact, an alternative TGase-2 transcript was shown to be expressed in cells upon their treatment with cytokines, and interestingly, was also detected in the brains of Alzheimer's patients (29)(30)(31).…”

mentioning

confidence: 99%

“…The carboxyl-terminal truncation that generates the TGase-S protein removes a portion of its guanine nucleotide-binding domain, as well as its binding site for phospholipase-Cδ1, and results in enhanced protein aggregation (28,32,33). Thus, in the present study, we have set out to determine whether the selective abrogation of TGase-2's GTP-binding capability might be sufficient to give rise to apoptotic activity.…”

mentioning

confidence: 99%

See 1 more Smart Citation

GTP-Binding-Defective Forms of Tissue Transglutaminase Trigger Cell Death

2007

Self Cite

View full text Add to dashboard Cite

Tissue transglutaminase (TGase-2), which binds GTP and catalyzes the crosslinking of proteins (transamidation), has been implicated both in the promotion of cell death and in the protection of cells against apoptotic insults. However, a novel transcript originally identified from the brains of Alzheimer's patients, encoding a truncated form of TGase-2 (called TGase-S), shows strong apoptotic activity. TGase-S exhibits no detectable GTP-binding capability, suggesting that its ability to induce cell death might be due to its inability to bind GTP. Thus, we have examined whether eliminating the GTP-binding capability of full-length human TGase-2 would prevent it from conferring protection against apoptotic challenges and instead convert it into a protein that causes cell death. A number of point mutants of human TGase-2 defective for binding GTP, as well as a mutant that shows impaired GTP-hydrolytic activity, were generated. Similar to what we had found for TGase-S, there was a time-dependent decrease in the expression of the GTP-binding-defective TGase-2 mutants in different cell lines, whereas the expression of wild-type TGase-2 and the GTP hydrolysis-defective mutant was sustained. Moreover, the GTP-binding-defective TGase-2 mutants induced cell death. The cell death responses triggered by these mutants were not due to their transdamidation activity, because double-mutants that were both GTP-binding-and transamidationdefective also stimulated cell death. Therefore, these results point to the inability to bind GTP as being sufficient for the apoptotic activity exhibited by the TGase-S protein. They also highlight a novel example of how the loss of GTP-binding activity can convert a protein that provides protection against apoptotic stimuli into a cell death-promoting factor. KeywordsGTP; signaling; transglutaminase; apoptosis; Alzheimer's; transamidation Tissue transglutaminase (TGase-2) belongs to a family of enzymes (transglutaminases) that catalyze the Ca 2+ -dependent, post-translational modification of proteins through the incorporation of polyamines or the formation of covalent crosslinks (1-4). The underlying chemical reaction involves the generation of an isopeptide bond between the γ-carboxamide group of a peptide-bound glutamine residue and either the ε-amino group of a lysine residue or the primary amino group of a polyamine. The expression of TGase-2 and its accompanying transamidation activity are stimulated when cells are exposed to different stresses, differentiation agents, and growth factors (5-11). A number of reports have suggested that TGase-2 is able to both promote and prevent apoptosis (4,12). For example, studies performed † This work was supported by GM61762. *To whom correspondence should be addressed. These authors contributed equally to this work. (6,7,(14)(15)(16)(17)(18)(19)(20)(21)(22). On the other hand, the regulation of TGase-2 by growth and differentiation factors has also been shown to be important in conferring a survival advantage to cells challenged with apoptotic...

show abstract

Calcium‐dependent activation of transglutaminase 2 by nanosecond pulsed electric fields

Morotomi-Yano

Yano

2017

FEBS Open Bio

View full text Add to dashboard Cite

Exposure of cultured human cells to nanosecond pulsed electric fields (nsPEFs) elicits various cellular events, including Ca 2+ influx and cell death. Recently, ns PEF s have been regarded as a novel physical treatment useful for biology and medicine, but the underlying mechanism of action remains to be fully elucidated. In this study, we investigated the effect of ns PEF s on transglutaminases ( TG s), enzymes that catalyze covalent protein modifications such as protein–protein crosslinking. Cellular TG activity was monitored by conjugation of cellular proteins with biotin‐cadaverine, a cell‐permeable pseudosubstrate for TG s. We applied ns PEF s to HeLa S3 cells and found that overall catalytic activity of cellular TG s was greatly increased in a Ca 2+ ‐dependent manner. The Ca 2+ ionophore ionomycin significantly augmented ns PEF ‐induced TG activation, further supporting the importance of Ca 2+ . Among human TG family members, TG 2 is known to be the most ubiquitously expressed, and its catalytic activity requires elevated intracellular Ca 2+ . Given the requirement of Ca 2+ for TG activation by ns PEF s, we performed depletion of TG 2 by RNA interference ( RNA i). We observed that TG 2 RNA i suppressed the ns PEF ‐induced TG activation and partially alleviated the cytotoxic effects of ns PEF s. These findings demonstrate that TG 2 activation is a Ca 2+ ‐dependent event in ns PEF ‐exposed cells and exerts negative effects on cell physiology.

show abstract

Two isoforms of tissue transglutaminase mediate opposing cellular fates

Cited by 97 publications

References 32 publications

Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-κB activity in hypoxic tumor cells

Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-κB activity in hypoxic tumor cells

GTP-Binding-Defective Forms of Tissue Transglutaminase Trigger Cell Death

Calcium‐dependent activation of transglutaminase 2 by nanosecond pulsed electric fields

Contact Info

Product

Resources

About