Expression of tissue transglutaminase in the developing chicken limb is associated both with apoptosis and endochondral ossification

Thomázy, Vilmos; Davies, Peter J.

doi:10.1038/sj.cdd.4400464

Cited by 38 publications

(33 citation statements)

References 41 publications

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“…Expression of transglutaminase 2 has been associated with apoptosis during development with formation of the interdigital web and myoblasts (13) and during embryo implantation and postpartum involution of the uterine epithelium (14). Transglutaminase 2 expression increases significantly in response to apoptotic stimuli in a number of cell types.…”

Section: Discussionmentioning

confidence: 99%

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Choi

Khosla

et al. 2005

Molecular Cancer Therapeutics

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Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion. We have identified the novel finding that treatment of glioblastoma cells with transglutaminase 2 inhibitors promotes cell death and enhances sensitivity to chemotherapy. 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. Treatment with these transglutaminase 2 inhibitors resulted in markedly decreased levels of the prosurvival protein, phosphorylated Akt, and its downstream targets. These changes promote a proapoptotic profile with altered levels of multiple intracellular proteins that determine cell survival. These changes include decreased levels of the antiapoptotic proteins, survivin, phosphorylated Bad, and phosphorylated glycogen synthetase kinase 3B (GSK-3B), and increased levels of the proapoptotic BH3-only protein, Bim. In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-NV -bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone. Groups treated with transglutaminase 2 inhibitors showed an increased incidence of apoptosis determined with deoxynucleotidyl transferasemediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas. [Mol Cancer Ther 2005;4(9):1293 -302]

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Section: Discussionmentioning

confidence: 99%

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Choi

Khosla

et al. 2005

Molecular Cancer Therapeutics

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“…RGDindependent cell adhesion mediated by matrix-bound TG2-syndecan-4 interactions could be physiologically relevant in tissue remodeling during differentiation and/or after wounding (7,47). Both these events are known to cause up-regulation and secretion of TG2 (44,48) and involve remodeling of the matrix by numerous proteases.…”

Section: Discussionmentioning

confidence: 99%

Fibronectin-Tissue Transglutaminase Matrix Rescues RGD-impaired Cell Adhesion through Syndecan-4 and β1 Integrin Co-signaling

Telci

Wang

et al. 2008

Journal of Biological Chemistry

120

165

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Heterotropic association of tissue transglutaminase (TG2) with extracellular matrix-associated fibronectin (FN) can restore the adhesion of fibroblasts when the integrin-mediated direct binding to FN is impaired using RGD-containing peptide. We demonstrate that the compensatory effect of the TG-FN complex in the presence of RGD-containing peptides is mediated by TG2 binding to the heparan sulfate chains of the syndecan-4 cell surface receptor. This binding mediates activation of protein kinase C␣ (PKC␣) and its subsequent interaction with ␤ 1 integrin since disruption of PKC␣ binding to ␤ 1 integrins with a cell-permeant competitive peptide inhibits cell adhesion and the associated actin stress fiber formation. Cell signaling by this process leads to the activation of focal adhesion kinase and ERK1/2 mitogen-activated protein kinases. Fibroblasts deficient in Raf-1 do not respond fully to the TG-FN complex unless either the full-length kinase competent Raf-1 or the kinase-inactive domain of Raf-1 is reintroduced, indicating the involvement of the Raf-1 protein in the signaling mechanism. We propose a model for a novel RGD-independent cell adhesion process that could be important during tissue injury and/or remodeling whereby TG-FN binding to syndecan-4 activates PKC␣ leading to its association with ␤ 1 integrin, reinforcement of actin-stress fiber organization, and MAPK pathway activation. Tissue transglutaminase (TG2)2 belongs to a family of enzymes that in the presence of Ca 2ϩ catalyze the post-translational modification of proteins either by covalent cross-linking or through the incorporation of primary amines. TG2 has a GTP binding/hydrolysis site that negatively modulates the Ca 2ϩ -dependent transamidating activity of the enzyme by obstructing access to the active site (1). As a consequence, the enzyme is likely to be inactive under normal Ca 2ϩ homeostasis. TG2 localizes mainly in the cytoplasm, yet recent reports also suggest its presence in the nucleus, mitochondria, at the cell surface, and in the extracellular matrix (ECM) (1-3). TG2 is translocated to the plasma membrane and was subsequently deposited into the ECM via a non-classical secretory mechanism reportedly dependent on active site conformation and on an intact N-terminal ␤-sandwich domain (4, 5) as well as on its possible association with integrins (6). Deposition of the enzyme into the ECM after cell damage and stress is important in the remodeling and/or stabilization of the several ECM proteins, such as FN (7,8). FN is particularly interesting since TG2 binds to this ECM protein with high affinity promoting wideranging effects on cell-matrix interactions, including the regulation of cell adhesion and migration, matrix assembly, and adhesion-dependent signaling (6,7,9).Cell adhesion to FN involves a series of coordinated signaling events orchestrated by numerous transmembrane receptors including the integrins and the superfamily of cell-surface proteoglycans (10, 11). The identity of the receptor-ligand pairing defines the composition of f...

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“…11,12,24,25 During myogenesis in vitro, as many as 50% of myoblasts reportedly undergo apoptosis, 9,10,15 although the extent of cell death likely depends on origin of the myoblasts and the culture conditions used for each study. Myoblasts may undergo apoptosis during myogenesis as a means of regulating muscle size.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin F2α promotes muscle cell survival and growth through upregulation of the inhibitor of apoptosis protein BRUCE

Jansen

Pavlath

2008

Cell Death Differ

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During skeletal muscle growth and regeneration, the majority of differentiating myoblasts undergoes cell-cell fusion to form multinucleated myofibers, whereas a proportion of myoblasts undergoes apoptosis. The treatment of myoblasts with prostaglandin F2a (PGF2a) during myogenesis in vitro leads to the formation of large myotubes, but the mechanism by which PGF2a promotes myotube growth has not been investigated. Here, we demonstrate that PGF2a reduces cell death during myogenesis in vitro and in vivo. In addition, we show that PGF2a increases expression of the inhibitor of apoptosis protein (IAP) BRUCE through a pathway dependent on the nuclear factor of activated T cell 2 transcription factor. Importantly, PGF2a-mediated reduction in muscle cell death is dependent on BRUCE, and overexpression of BRUCE is sufficient to promote muscle cell survival and growth. These results establish a previously unrecognized link between NFAT signaling and regulation of IAP expression and are the first to identify a signaling pathway that increases BRUCE expression. In addition, our results provide evidence that increasing the pool of muscle cells available for fusion by inhibiting cell death enhances myotube growth.

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Expression of tissue transglutaminase in the developing chicken limb is associated both with apoptosis and endochondral ossification

Cited by 38 publications

References 41 publications

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Fibronectin-Tissue Transglutaminase Matrix Rescues RGD-impaired Cell Adhesion through Syndecan-4 and β1 Integrin Co-signaling

Prostaglandin F2α promotes muscle cell survival and growth through upregulation of the inhibitor of apoptosis protein BRUCE

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