Transglutaminase 2 at the Crossroads between Cell Death and Survival

Piacentini, Mauro; D’Eletto, Manuela; Falasca, Laura; Farrace, Maria Grazia; Rodolfo, Carlo

doi:10.1002/9781118105771.ch5

Cited by 21 publications

(11 citation statements)

References 265 publications

(289 reference statements)

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“…TGM2 is expressed in all organs and is the most ubiquitous of all the transglutaminases [41]. It has also been well documented in other tissues that TGM2 mRNA coincides with apoptosis in vivo , such as the liver [42].…”

Section: Discussionmentioning

confidence: 99%

Changes in granulosa cells gene expression associated with growth, plateau and atretic phases in medium bovine follicles

Douville

Sirard

2014

J Ovarian Res

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BackgroundThe objective of this study was to build the transcriptomic profile of granulosa cells originating from follicles 6 to 9 mm in diameter in dairy cattle using microarrays.MethodsGranulosa cells originating from three different phases of antral follicle growth were compared: growing (G), plateau (P) and atresia (A), as categorized by flow cytometry profiles of DNA. The growing and atretic conditions were each hybridized against the plateau condition as a reference in order to understand the specific biological mechanisms modulated in this class of follicles.Results2,942 genes were differentially expressed (P < 0.05) in P vs. G and 1,974 in A vs. P. A clear segregation of the 3 phases was confirmed by between group analysis (BGA). The first characteristic of the plateau phase is the activation of the upstream regulators TP53 and PTEN which participate in the reduction of cell growth through MYC, FOS and E2F1-2-3. We also observed the down-regulation of steroidogenesis genes: CYP11A1 and CYP19A1, in the granulosa cells of the plateau phase relative to the growth phase. On the other hand, the A vs. P contrast showed up-regulation of multiple transcripts associated to apoptosis: CCT2, DAB2, DSG2 and TGM2.ConclusionsThis study offers multiple candidate genes to be further studied in order to elucidate their role in the modulation of follicular development and, ultimately, of oocyte quality.

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Section: Discussionmentioning

confidence: 99%

Changes in granulosa cells gene expression associated with growth, plateau and atretic phases in medium bovine follicles

Douville

Sirard

2014

J Ovarian Res

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“…The ubiquitously expressed transglutaminase 2 (TG2) is the most widely studied member of the TG family, which has been implicated in the regulation of a wide range of cellular processes, including cell adhesion, migration, growth, survival, apoptosis, differentiation and extracellular matrix organization (Nurminskaya and Belkin, ). The role of TG2 in cell survival and cell death is cell‐specific with initial findings suggesting that TG2 was pro‐apoptotic; however, more recent data indicate that TG2 has a role in cell survival (Piacentini et al ., ). Dysregulation of TG2 has been implicated in much pathology, including celiac disease, neurodegenerative disorders, some cancers and as such represents a potential therapeutic target (Caccamo et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Modulation of transglutaminase 2 activity in H9c2 cells by PKC and PKA signalling: a role for transglutaminase 2 in cytoprotection

Almami

Dickenson

Hargreaves

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSETissue transglutaminase (TG2) has been shown to mediate cell survival in many cell types. In this study, we investigated whether the role of TG2 in cytoprotection was mediated by the activation of PKA and PKC in cardiomyocyte-like H9c2 cells. EXPERIMENTAL APPROACHH9c2 cells were extracted following stimulation with phorbol-12-myristate-13-acetate (PMA) and forskolin. Transglutaminase activity was determined using an amine incorporating and a protein crosslinking assay. The presence of TG isoforms (TG1, 2, 3) was determined using Western blot analysis. The role of TG2 in PMA-and forskolin-induced cytoprotection was investigated by monitoring H2O2-induced oxidative stress in H9c2 cells. KEY RESULTSWestern blotting showed TG2 >> TG1 protein expression but no detectable TG3. The amine incorporating activity of TG2 in H9c2 cells increased in a time and concentration-dependent manner following stimulation with PMA and forskolin. PMA and forskolin-induced TG2 activity was blocked by PKC (Ro 31-8220) and PKA (KT 5720 and Rp-8-Cl-cAMPS) inhibitors respectively. The PMA-and forskolin-induced increases in TG2 activity were attenuated by the TG2 inhibitors Z-DON and R283. Immunocytochemistry revealed TG2-mediated biotin-X-cadaverine incorporation into proteins and proteomic analysis identified known (β-tubulin) and novel (α-actinin) protein substrates for TG2. Pretreatment with PMA and forskolin reversed H2O2-induced decrease in MTT reduction and release of LDH. TG2 inhibitors R283 and Z-DON blocked PMA-and forskolin-induced cytoprotection. CONCLUSIONS AND IMPLICATIONSTG2 activity was stimulated via PKA-and PKC-dependent signalling pathways in H9c2 cells These results suggest a role for TG2 in cytoprotection induced by these kinases. AbbreviationsMTT, (3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); PMA, phorbol-12-myristate-13-acetate; TG2, transglutaminase type 2

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“…[15][16][17][18][19] Given the TG2 ubiquitous expression and variety of enzymatic and nonenzymatic activities, it is not surprising that this protein appears intimately involved in the regulation of numerous cell functions including cell adhesion, migration, survival and death, exocytosis and more recently autophagy. 20 We have shown that the TG2 protein deletion, both in vivo and in mouse embryonic fibroblasts, results in the accumulation of LC3 II on preautophagic vesicles. [21][22][23] We have also demonstrated that TG2 regulation of autophagy occurs by its transamidating activity 24 and its inhibition results in the intracellular increase of ubiquitinated protein aggregates.…”

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confidence: 93%

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

et al. 2014

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Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. Here we demonstrate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria. In TG2-ablated cells we observed the presence of a large number of fragmented mitochondria that display decreased membrane potential, downregulation of IF1 along with increased Drp1 and PINK1 levels, two key proteins regulating the mitochondrial fission. Of note, we demonstrate that in healthy mitochondria, TG2 interacts with the dynamic proteins Drp1 and Fis1; interestingly, their interaction is largely reduced upon induction of the fission process by carbonyl cyanide m-chlorophenyl hydrazine (CCCP). In keeping with these findings, mitochondria lacking TG2 are more susceptible to CCCP treatment. As a consequence of accumulation of damaged mitochondria, cells lacking TG2 increased their aerobic glycolysis and became sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). In contrast, TG2-proficient cells are more resistant to 2-DG-induced apoptosis as the caspase 3 is inactivated through the enzyme's crosslinking activity. The data presented in this study show that TG2 plays a key role in cellular dynamics and consequently influences the energetic metabolism.

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Transglutaminase 2 at the Crossroads between Cell Death and Survival

Cited by 21 publications

References 265 publications

Changes in granulosa cells gene expression associated with growth, plateau and atretic phases in medium bovine follicles

Changes in granulosa cells gene expression associated with growth, plateau and atretic phases in medium bovine follicles

Modulation of transglutaminase 2 activity in H9c2 cells by PKC and PKA signalling: a role for transglutaminase 2 in cytoprotection

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

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