Disease relevance of TGM1

• We recently mapped the disease locus for severe autosomal recessive lamellar ichthyosis (LI) to chromosome 14q11 and showed complete linkage with TGM1, the gene encoding transglutaminase 1 [1].
• Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies [2].
• It was recently shown that mutations in the transglutaminase 1 (TGM1) gene may be associated with the clinical subtypes lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (CIE) [3].
• Expression of keratinocyte transglutaminase (TGM1) is critical for maturation of mammalian epidermis and occurs during squamous metaplasia [4].
• Treatment of human neuroblastoma SH-SY5Y cells with retinoic acid (RA) resulted in a significant increase in tTG levels and in vitro TG activity [5].

Psychiatry related information on TGM1

• Intron-exon swapping of transglutaminase mRNA and neuronal Tau aggregation in Alzheimer's disease [6].
• Most importantly, numerous studies have presented data demonstrating that dysregulation of TG2 may contribute to the pathogenesis of many neurodegenerative disorders, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis as well as nervous system injuries [7].
• The elution times of gum arabic solutions incubated with transglutaminase were unchanged over time, whereas incubation of sodium caseinate with transglutaminase resulted in shorter elution times as reaction time increased, indicating the formation of cross-linked caseinate polymers [8].
• Responses that were independently associated with TG-positive status were irritability/lethargy, abdominal distention/gas, and difficulty with weight gain [9].

High impact information on TGM1

• (2004) provide evidence that pathogenic actions of angiotensin II involve covalent crosslinking of angiotensin AT1 receptors by factor XIIIA transglutaminase, resulting in stable receptor dimers with enhanced signaling properties [10].
• The apoptotic cell death was partially suppressed by the transglutaminase inhibitors cystamine and monodansyl cadaverine (but not putrescine), suggesting involvement of a transglutaminase reaction and providing a potential basis for the development of therapeutic measures for CAG-repeat expansion diseases [11].
• Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch [11].
• We have now identified point mutations in TGM1 in two of the multiplex LI families used in the linkage study [1].
• Within the transglutaminase family, these arginines are invariant within a conserved region, distant from the catalytic site of the enzyme [1].

Chemical compound and disease context of TGM1

• Conclusions Pan-transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and cytokeratins 6 and 16 [12].
• Lamellar ichthyosis: response to etretinate with transglutaminase 1 recovery [13].
• For example, transglutaminase activity has been hypothesized to be involved in the pathogenetic mechanisms responsible for several human diseases, including neurodegenerative diseases, such as polyglutamine diseases hitherto identified [14].
• To address this issue, we have used two experimental settings: carbon tetrachloride (CCl(4))-induced liver injury in wild-type and TG2 knockout mice; and liver biopsies obtained from a large cohort of hepatitis C virus (HCV)-infected patients [15].
• In order to understand the mechanism for insoluble neurotoxic protein polymerization in Alzheimer's disease (AD) brain neurons, we examined protein and gene expression for transglutaminase (TGase 2; tissue transglutaminase (tTG)) in hippocampus and isocortex [6].

Biological context of TGM1

• Interestingly, the positions of these introns have been conserved in comparison with the genes of two other transglutaminase-like activities described in the literature, but the TGM1 gene is by far the smallest characterized to date because its introns are relatively smaller [16].
• Examination of the TGM1 5'-flanking region in transient transfections of human epidermal cells revealed an AP1 site approximately 1.5kb upstream from the transcription start site and a CRE site approximately 0.5kb upstream that, combined, accounted for as much as 90% of the transcriptional activity [4].
• Three individuals homozygous for the common haplotype, two affected by LI and one affected by CIE, were analysed for mutations in the TGM1 gene [3].
• We found families in which the splice acceptor site mutation was homozygous, and families where the patients were compound heterozygotes for the splice acceptor site mutation and another TGM1 mutation [2].
• Our analyses of patients with CRI revealed a common TGM1 mutation involving loss of the intron 5 splice acceptor site leading to alternative splicing of the message [2].

Anatomical context of TGM1

• Use of human-rodent cell hybrid panels and chromosomal in situ hybridization with biotin-labeled probes revealed that the human TGM1 gene maps to chromosome position 14q11.2-13 [16].
• Complexes of transglutaminase with integrins are formed inside the cell during biosynthesis and accumulate on the surface and in focal adhesions [17].
• The amino acid sequences of factor XIII, TGC, and TGK establish them as a homologous gene family and also reveal a striking homology to the erythrocyte membrane protein, band 4 [18].
• Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses [19].
• Western blot analysis clearly indicated that the active TG was tTG and immunocytochemistry showed it be situated in the cytosol of the cells [20].

Associations of TGM1 with chemical compounds

• While the expression of the TGM1 gene is markedly affected by the calcium concentration of the medium, all trans retinoic acid, vitamin D3, and TPA treatment, the expression of the RABGGTA gene was unaffected by these reagents [21].
• Here we report that cell surface transglutaminase mediates adhesion and spreading of cells on the 42-kD fibronectin fragment, which lacks integrin-binding motifs [17].
• To examine the effects of GTP on in situ TG activity, tiazofurin, a drug that selectively decreases GTP levels, was used [5].
• We found that sphingosylphosphocholine (lyso-SM) was the only lipid to activate transglutaminase at low Ca2+ concentrations [22].
• TG activity was also increased in response to activation of muscarinic cholinergic receptors, which increases intracellular calcium through inositol 1,4,5-trisphosphate generation [5].

Physical interactions of TGM1

• The presence of a nonpeptidyl transglutaminase inactivator rendered the cells more susceptible to detachment by trypsin and destabilized the association of fibronectin with the subendothelial extracellular matrix [23].
• Transglutaminase 2 (TG2) is a GTP-binding protein with transglutaminase activity [24].
• In Celiac Disease, a Subset of Autoantibodies against Transglutaminase Binds Toll-Like Receptor 4 and Induces Activation of Monocytes [25].
• In this study, we demonstrate that LTBP-1 and large latent complex are substrates for transglutaminase [26].
• In this study we found that lysoPC in non-toxic concentrations caused increased activator protein-1 (AP-1) DNA-binding activity and transglutaminase-1 expression in cultured human keratinocytes [27].

Enzymatic interactions of TGM1

• Tissue transglutaminase (tTG) catalyzes a Ca(2+)-dependent transglutaminase (TGase) activity that stabilizes tissues and a GTP hydrolysis activity that regulates cell receptor signaling [28].
• Transglutaminase catalyzes differential crosslinking of small heat shock proteins and amyloid-beta [29].
• Tg localized in fibroblast membranes was also shown to catalyze the formation of native IGFBP-1 multimers, however, Q66A/Q67A IGFBP-1 failed to polymerize [30].
• Recombinant human PAI-2 was labeled with [14C]putrescine catalyzed by guinea pig liver transglutaminase [31].
• These results suggest that, following non-covalent association of plasminogen with the HUVEC surface, cell surface-associated transglutaminase catalyzes cross-linking of plasminogen into large molecular mass aggregates that can be converted into functional plasmin [32].

Co-localisations of TGM1

• In cultured FRC, TG is induced 5- to 20-fold and becomes colocalized with matrix proteins by treatment with interleukin-4, but not by other cytokines that are commonly increased in lymph upon immune activation [33].
• Our laboratory previously demonstrated that huntingtin protein colocalizes with transglutaminase 2 and its product, the epsilon-(gamma-glutamyl)lysine bond in intranuclear inclusions in HD frontal cortex [34].

Regulatory relationships of TGM1

• In contrast, basal in situ TG activity did not increase concurrently with RA-induced increased tTG levels [5].
• During terminal differentiation, involucrin becomes covalently cross-linked to other proteins by a membrane-anchored calcium-activated transglutaminase (TG) to form part of the cornified envelope [35].
• In the present study we show that S100A11 forms multimers when cultured keratinocytes are challenged by increased levels of intracellular calcium and that multimer formation is inhibited by the TG inhibitor, cystamine [36].
• HOXA7 overexpression repressed transglutaminase 1-reporter activity [37].
• The AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin also up-regulated keratinocyte TGM1 mRNA in a concentration- and time-dependent manner [38].

Other interactions of TGM1

• Beta ig-h3 induces keratinocyte differentiation via modulation of involucrin and transglutaminase expression through the integrin alpha3beta1 and the phosphatidylinositol 3-kinase/Akt signaling pathway [39].
• Structure and organization of the human transglutaminase 3 gene: evolutionary relationship to the transglutaminase family [40].
• Even though TGM1 and RABGGTA have different functions, their close localization raised the question as to whether they are functionally related in the epidermis [21].
• Of the 607 SNPs, 284 were identified in CYP genes, 302 in esterase genes, and 21 in the other two genes ( GGT1, and TGM1); overall, 37 SNPs were located in 5' flanking regions, 496 in introns, 55 in exons, and 19 in 3' flanking regions [41].
• Mutations in any of the three known causative genes, TGM1, ALOXE3 or ALOX12B, can lead either to NBCIE or LI [42].

Analytical, diagnostic and therapeutic context of TGM1

• While immunofluorescence microscopy was negative in patients with non-sense mutations or out-of-frame insertions or deletions, the results were variable in cases with mis-sense mutations and in cases with no mutations in the TGM1 gene [43].
• No TGM1 mutation was found in any of the four families by direct sequence analysis [44].
• A full-length cDNA for the novel transglutaminase (TGX) was obtained by anchored PCR [45].
• Factor XIIIa, tissue and keratinocyte transglutaminase protein content, and mRNA expression in the colon were evaluated by western blot analysis and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively [46].
• Quantitative evaluation of transglutaminase (TG) activity determined using the [1,4 14C]-putrescine incorporation assay showed that the enzyme was active in all cell types [20].

References