Disease relevance of Tgm1

• Retinoid analogs altered the expression of the initial TGase peak in both CHO and melanoma cells [1].
• Dimethyl sulfoxide-induced transglutaminase activity in murine-derived Friend erythroleukemia cells [2].
• Transglutaminase 1 (TGase 1) is one of the genes implicated in autosomal recessive congenital ichthyosis [3].
• Deficient cross-linking of the cell envelope in some patients with the autosomal recessive skin disorder lamellar ichthyosis (LI) and several mutations of the TGase 1 gene that have been identified in families with LI suggest the importance of this gene in production of the cell envelope [4].
• It was also observed that TG2(-/-) mice exhibited increased neutrophil phagocytic activity, but had attenuated neutrophil chemotaxis and impaired neutrophil extravasation with higher neutrophil counts in their circulation during yeast extract-induced peritonitis [5].

Psychiatry related information on Tgm1

• 'Tissue' transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington's disease [6].
• Several lines of evidence suggest that transglutaminase may cross-link tau into stable, insoluble aggregates, leading to the formation of NFTs in Alzheimer's disease and progressive supranuclear palsy [7].

High impact information on Tgm1

• Inhibition of TGase provides a new treatment strategy for HD and other polyglutamine diseases [8].
• Cystamine given intraperitoneally entered brain where it inhibited TGase activity [8].
• We suggest that the ichthyosiform skin phenotype in TGase 1 deficiency develops the massive hyperkeratosis as a physical compensation for the defective cutaneous permeability barrier required for survival in a terrestrial environment [3].
• Transglutaminase (glutaminyl-peptide gamma-glutamyltransferase, EC 2.3.2.13) (TGase) activity was detected in the lysates of uninduced FL cells and was markedly increased in DMSO-treated cells [2].
• These results suggest that the increase in TGase activity in DMSO- or butyric acid-treated FL cells may be related to cell differentiation [2].

Chemical compound and disease context of Tgm1

• In mouse melanoma cells, retinoic acid plus MSH markedly enhanced the activity of the initial TGase peak compared to MSH alone [1].
• The retinoic acid induction of transglutaminase was accompanied by increased phosphatidylinositol turnover and phosphatidic acid generation, which were efficiently suppressed by prior exposure of cells to pertussis toxin [9].
• Treatment with either the competitive transglutaminase 2 inhibitor, monodansylcadaverine, or with highly specific small-molecule transglutaminase 2 inhibitors, KCA075 or KCC009, results in induction of apoptosis in glioblastoma cells [10].
• In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-N'-bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone [10].
• TPA-effects suppressible by bryostatin 1 include the Ca2+-dependent stimulation of arachidonic acid and prostaglandin E2 release, of ornithine decarboxylase (ODC) activity and ODC-mRNA expression and of transglutaminase activity in keratinocytes in vivo and/or in vitro and, in addition, Epstein-Barr virus induction in Raji cells [11].

Biological context of Tgm1

• TGase 2 expression has been associated with apoptosis, and it has been proposed that its activation should lead to the irreversible assembly of a cross-linked protein scaffold in dead cells [12].
• The transglutaminase transgene is expressed in cartilage, the cells of the apical ectodermal ridge, and in regions of apoptotic cell death of the interdigital mesenchyme [13].
• In embryos made transgenic with a transglutaminase promoter-beta-galactosidase reporter gene, the transgene shows specific patterns of expression during limb development [13].
• Subcellular fractionation revealed a relatively constant particulate isoform of TGase activity which predominated in early embryonic muscle development [14].
• Facilitated wound healing by activation of the Transglutaminase 1 gene [15].

Anatomical context of Tgm1

• Retinol increased the activity of TGase 1 hr after release in CHO cells, and the activity remained elevated until hr 4 [1].
• Induction of apoptosis ex vivo in TGase 2(-/-) thymocytes (by CD95, dexamethasone, etoposide, and H(2)O(2)) and in vitro on TGase 2(-/-) mouse embryonal fibroblasts (by retinoids, UV, and H(2)O(2)) showed no significant differences [12].
• TGase activity measured on liver and thymus extracts showed, however, a minimal residual activity in TGase 2(-/-) mice [12].
• Thus, TGase 2-catalyzed protein polymerization contributes to the ultrastructural changes typical of dying apoptotic cells; it stabilizes the integrity of the apoptotic cells, preventing the release of harmful intracellular components into the extracellular space and, consequently, inflammation and scar formation [12].
• TG activity was low in prenatal mouse forebrain but increased fivefold to peak at P0, which corresponds with the beginning of the mouse BGS [16].

Associations of Tgm1 with chemical compounds

• Retinoic acid alone also increased TGase activity biphasically in these cells without the addition of MSH [1].
• These studies suggest that retinoid effects that increase TGase activity may alter the ODCase expression in proliferation and differentiation [1].
• Transglutaminase 2 (TGase 2), or tissue transglutaminase, catalyzes either epsilon-(gamma-glutamyl)lysine or N(1), N(8)-(gamma-glutamyl)spermidine isopeptide bonds [12].
• Moreover, administration of the transglutaminase inhibitor cystamine delays the onset of pathology in the R6/2 HD mouse model [17].
• Coagulation Factor XIII (F. VIII), a member of the transglutaminase (TGase) superfamily, is activated by thrombin, cross-links fibrin and stabilizes clots [14].

Physical interactions of Tgm1

• Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion [10].

Co-localisations of Tgm1

• The TGase 1 enzyme co-localized on the plasma membrane of migrating keratinocytes with involucrin, but not with loricrin, which suggests the premature assembly of the cornified envelope [15].
• The transglutaminase-related antigen was shown by confocal microscopy to co-localize only with nonbasal cell specific keratin intermediate filaments [18].

Regulatory relationships of Tgm1

• Retinoids increase transglutaminase activity and inhibit ornithine decarboxylase activity in Chinese hamster ovary cells and in melanoma cells stimulated to differentiate [1].
• Instead of enhancing these parameters, EGF inhibited RA-induced TGase expression [19].
• These findings demonstrate that TGase may serve as a survival factor and RA-induced TGase expression requires the activation of PI3K but is antagonized by the Ras-ERK pathway [19].
• Similarly, S. chromofuscus PLD stimulated transglutaminase activity more effectively and potently than S. sp. PLD [20].
• Phospholipase d signaling and extracellular signal-regulated kinase-1 and -2 phosphorylation (activation) are required for maximal phorbol ester-induced transglutaminase activity, a marker of keratinocyte differentiation [21].
• Overexpression of Stat-3, JAK2, and/or TGase-1 in RPTC revealed that JAK2 is indispensable for TGase-1 to induce Stat-3 phosphorylation and TGase-1 potentiates JAK2-induced Stat-3 phosphorylation [22].

Other interactions of Tgm1

• Transglutaminase and clusterin induction during normal and abnormal limb development in the mouse [23].
• On the other hand, the peak cytosolic TGase activity occurs in the neonatal period, correlating temporally with muscle prothrombin expression during activity-dependent synapse elimination and possibly the source of the enzyme localized to the NMJ extracellular matrix resulting in synaptic stabilization [14].
• As the substrates of TGase 1, chronic UVR induced the up-regulation of filaggrin and loricrin in mouse epidermis as well [24].
• In neonatal mouse skin, TGase 1 mRNA as well as keratin 6alpha was induced in the epidermis at the wound edges as early as 2 hours after injury and that expression continued in the migrating epidermis until completion of re-epithelialization [15].
• Activation of transglutaminase in mu-calpain null erythrocytes [25].

Analytical, diagnostic and therapeutic context of Tgm1

• In both cell culture lines, we detected a biphasic increase in TGase activity and a single peak of ODCase activity within 7 hr after release or stimulation [1].
• Complete absence of TGase 2 was demonstrated by reverse transcription-PCR and Western blot analysis [12].
• PCR analysis of mRNA extracted from the same tissues demonstrated that at least TGase 1 (normally present in the skin) is also expressed in these tissues and contributes to this residual activity [12].
• Immunoblotting of the isolated junctional fraction revealed that transglutaminase type 1 was concentrated in the fraction not only as a 97-kDa form but also as forms of various molecular masses cross-linked to other proteins [26].
• Coculture of PM with amphotericin B (AmpB) inhibited the serum-induced expression and accumulation of tissue TGase [27].

References