Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation

Yeo, Shi Yun; Itahana, Yoko; Guo, Alvin Kunyao; Han, Rachel; Iwamoto, Kozue; Nguyen, Hung Thanh; Bao, Yongping; Kleiber, K.; Wu, Yajun; Bay, Boon Huat; Voorhoeve, Mathijs; Itahana, Koji

doi:10.7554/elife.07101

Cited by 21 publications

(19 citation statements)

References 104 publications

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“…The inhibition of autophagic flux under hyperammonemia could well explain the increase in the levels of LC3 and of the transglutaminase TGM2 in vitro and in vivo models as well as in post mortem brain samples of liver cirrhosis patients with HE. An upregulation at the mRNA level of TGM2 as observed here in HE patients indicates a response to counteract the effects of ammonia-induced stress as TGM2 is known to promote autophagy [35]. The increase in TGM2 was well recapitulated when analyzing in vitro and in vivo HE models.…”

Section: Discussionsupporting

confidence: 63%

“…Transglutaminase 2 (TGM2) is strongly upregulated under various stress conditions including tissue injury, inflammation, protein misfolding, and oxidative stress and was shown to positively regulate late steps of autophagy [35],[36]. We checked whether protein levels of TGM2 were increased in cultured rat astrocytes upon treatment with NH 4 Cl and whether TGM2 could be used as an additional marker of altered autophagy.…”

Section: Resultsmentioning

confidence: 99%

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Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes

Zimmermann

Görg

et al. 2019

EBioMedicine

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BackgroundHepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients.MethodsUsing primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an in vivo rat HE model, and post mortem brain samples of liver cirrhosis patients with HE we analyzed whether and how hyperammonemia modulates autophagy.FindingsWe show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an in vivo rat HE model. Transglutaminase 2 (TGM2), a factor promoting autophagy, is upregulated in astrocytes of in vitro- and in vivo-HE models as well as in post mortem brain samples of liver cirrhosis patients with HE, but not in patients without HE. LC3, a commonly used autophagy marker, is significantly increased in the brain of HE patients. Ammonia also modulated autophagy moderately in neuronal cells. We show that taurine, known to ameliorate several parameters caused by hyperammonemia in patients suffering from liver failure, is highly potent in reducing ammonia-induced impairment of autophagic flux. This protective effect of taurine is apparently not linked to inhibition of mTOR signaling but rather to reducing ammonia-induced ROS formation.InterpretationOur data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE.FundingSupported by the DFG, CRC974 “Communication and Systems Relevance in Liver Injury and Regeneration“, Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).

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Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes

Zimmermann

Görg

et al. 2019

EBioMedicine

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“…Whereas common apoptosis-related targets like Bax 41 and Noxa 42 were unchanged (Supplementary Fig. 9a, b), we detected a significant upregulation of Tgm2 43 , a protein of the transglutaminase family implicated in cellular differentiation 44 . Moreover, Par3 loss resulted in significant downregulation of the Wnt pathway component Disheveled 1 (Dvl1) 40 , in line with a reported role for Wnt signaling in keeping stemness of skin stem/progenitor cells 45 .…”

Section: Resultsmentioning

confidence: 76%

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

et al. 2019

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Epithelial homeostasis requires balanced progenitor cell proliferation and differentiation, whereas disrupting this equilibrium fosters degeneration or cancer. Here we studied how cell polarity signaling orchestrates epidermal self-renewal and differentiation. Using genetic ablation, quantitative imaging, mechanochemical reconstitution and atomic force microscopy, we find that mammalian Par3 couples genome integrity and epidermal fate through shaping keratinocyte mechanics, rather than mitotic spindle orientation. Par3 inactivation impairs RhoA activity, actomyosin contractility and viscoelasticity, eliciting mitotic failures that trigger aneuploidy, mitosis-dependent DNA damage responses, p53 stabilization and premature differentiation. Importantly, reconstituting myosin activity is sufficient to restore mitotic fidelity, genome integrity, and balanced differentiation and stratification. Collectively, this study deciphers a mechanical signaling network in which Par3 acts upstream of Rho/actomyosin contractility to promote intrinsic force generation, thereby maintaining mitotic accuracy and cellular fitness at the genomic level. Disturbing this network may compromise not only epidermal homeostasis but potentially also that of other self-renewing epithelia.

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“…The results indicate that ZBTB7A possibly plays an oncogenic role. Interestingly, we find that some genes have opposite effects in carcinogenesis, such as cellular retinoic acid binding protein 2 (CRABP2) [64, 65], epithelial membrane protein 3 (EMP3) [66, 67], transglutaminase 2 (TGM2) [68, 69], Yes associated protein 1 (YAP1) [70, 71], CDKN2A interacting protein (CDKN2AIP) [72], and BRCA2 and CDKN1A interacting protein (BCCIP) [73]. The genes can promote or inhibit cells growth in different conditions or stages of cancer (Supplementary Materials, Figure S3 and Table S1).…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNAs and Messenger RNAs Expression Profiles Potentially Regulated by ZBTB7A in Nasopharyngeal Carcinoma

Liu

Wei

Hao

et al. 2019

BioMed Research International

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Our previous studies showed that ZBTB7A played an important role in promoting nasopharyngeal carcinoma (NPC) progression. However, molecular mechanisms of different levels of ZBTB7A are still unclear. It is necessary to search molecular markers which are closely connected with ZBTB7A. We selected NPC sublines CNE2 with stably transfecting empty plasmid (negative control, NC) and short hair RNA (shRNA) plasmid targeting ZBTB7A as research objectives. Microarray was used to screen differentially expressed long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) via shRNA-CNE2 versus NC-CNE2. Quantitative PCR (qPCR) was used to validate lncRNAs and mRNAs from the sublines, chronic rhinitis, and NPC tissues. Bioinformatics was used to analyze regulatory pathways which were connected with ZBTB7A. The 1501 lncRNAs (long noncoding RNAs) and 1275 differentially expressed mRNAs were upregulated or downregulated over 2-fold. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the upregulated or downregulated carbohydrate and lipid metabolisms probably involved in carcinogenicity of shRNA-CNE2 (P-value cut-off was 0.05). In order to find the molecular mechanisms of ZBTB7A, we validated 12 differentially expressed lncRNAs and their nearby mRNAs by qPCR. Most of the differentially expressed mRNAs are closely connected with carbohydrate and lipid metabolisms in multiply cancers. Furthermore, part of them were validated in NPC and rhinitis tissues by qPCR. As a result, NR_047538, ENST00000442852, and fatty acid synthase (FASN) were closely associated with NPC. ZBTB7A had a positive association with NR_047538 and negative associations with ENST00000442852 and FASN. The results probably provide novel candidate biomarkers for NPC progression with different levels of ZBTB7A.

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Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation

Cited by 21 publications

References 104 publications

Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes

Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

Long Noncoding RNAs and Messenger RNAs Expression Profiles Potentially Regulated by ZBTB7A in Nasopharyngeal Carcinoma

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