Induction and activation of tissue transglutaminase during programmed cell death

Fésüs, László; Thomázy, Vilmos; Falus, András

doi:10.1016/0014-5793(87)80430-1

Cited by 449 publications

(204 citation statements)

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“…Tissue transglutaminase (TGase) has been shown to be upregulated in cells undergoing apoptosis, raising the possibility that it is a pro-apoptotic protein (7)(8)(9)(10)(13)(14)(15)(16). However, recent studies examining the role of TGase in RA-mediated differentiation have shown that it provides protection against apoptosis (12) and may be important for cellular differentiation (19,33).…”

Section: Resultsmentioning

confidence: 99%

“…The transamidation reaction of TGase has been well studied and consists of the Ca 2ϩ -dependent formation of covalent bonds between the ␥-carboxamide groups of peptide-bound glutamine residues and the primary amino groups of a wide variety of proteins (1,2). Transamidation has been implicated in a number of biological processes such as axonal regeneration, cellular differentiation, and apoptosis (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Many of the early studies of TGase have identified it as being present in cells and tissues undergoing apoptosis (7-10, 13, 14) and implicated the transamidation activity of TGase as a potentiator of programmed cell death (15,16).…”

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confidence: 99%

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Tissue Transglutaminase Protects against Apoptosis by Modifying the Tumor Suppressor Protein p110 Rb

Boehm

Singh

Combs

et al. 2002

Journal of Biological Chemistry

111

123

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Tissue transglutaminase or type II transglutaminase (TGase) 1 is an 87-kDa protein that contains two key catalytic activities, the ability to catalyze protein-amine cross-links and a GTP binding and hydrolysis activity. The transamidation reaction of TGase has been well studied and consists of the Ca 2ϩ -dependent formation of covalent bonds between the ␥-carboxamide groups of peptide-bound glutamine residues and the primary amino groups of a wide variety of proteins (1, 2). Transamidation has been implicated in a number of biological processes such as axonal regeneration, cellular differentiation, and apoptosis (3-12). Many of the early studies of TGase have identified it as being present in cells and tissues undergoing apoptosis (7-10, 13, 14) and implicated the transamidation activity of TGase as a potentiator of programmed cell death (15,16). However, there is growing evidence that TGase may not directly mediate apoptosis. TGase Ϫ/Ϫ mice showed no major developmental abnormalities, and the thymocytes from these mice were no less susceptible to apoptosis than TGase ϩ/ϩ cells (17,18). Studies examining the role of TGase in retinoic acid (RA)-mediated signaling (12), as well as studies demonstrating that TGase was required for neurite outgrowth (19), suggest that TGase may exhibit protective effects against apoptotic signals. It has been well documented that RA up-regulates both the expression and transamidation activity of TGase (12, 20 -22). We have recently shown that the ability of RA to up-regulate TGase expression and activity is required for the ability of RA to protect against apoptosis induced by a synthetic retinoid analog, all-trans-N-(4-hydroxyphenyl)retinamide (HPR) (12). The TGase-mediated inhibition of apoptosis appeared to involve its transamidation activity and its ability to bind GTP (12), a result that may suggest a role for TGase in more than one anti-apoptotic signaling pathway.To understand how TGase is acting as an anti-apoptotic factor, we set out to investigate substrates of TGase that are potential regulators of cell death. One such protein was the retinoblastoma gene product (Rb), a well established regulator of the G 1 /S checkpoint in the cell cycle (23)(24)(25). In addition to its role in cell cycle regulation and cellular differentiation, Rb has also been implicated in apoptosis (26). Rb Ϫ/Ϫ mice are embryonic lethal with significant apoptosis occurring in the developing nervous system and lens of the eye (27-30). The tumor suppressor gene p53 activates a pathway in response to various cellular insults that results in the degradation of Rb (31), a critical event that shifts cells toward apoptosis. The Rb protein was initially identified as a substrate for TGase-mediated transamidation in U937 cells in early stages of apoptosis (11). This finding, when combined with other results showing increased expression of TGase in apoptotic cells (7-10, 13, 14), led to the suggestion that TGase was a pro-apoptotic protein. However, we have found that TGase acts in a protective fashion (12) b...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Tissue Transglutaminase Protects against Apoptosis by Modifying the Tumor Suppressor Protein p110 Rb

Boehm

Singh

Combs

et al. 2002

Journal of Biological Chemistry

111

123

View full text Add to dashboard Cite

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“…TGase 2 is a calcium-dependent enzyme that catalyzes the formation of covalent bonds between free amine groups in one protein and protein-bound glutamines of another, creating highly cross-linked protein complexes (4). TGase 2 is ubiquitously expressed and has multiple normal physiologic functions through the targeting of specific substrates, such as blood clotting (5), wound healing (6), cell adhesion (7), apoptosis (8), and barrier formation (9). TGase 2 has also been associated with certain pathologic conditions [i.e., inflammatory diseases, such as encephalomyelitis (10), inflammatory myopathies (11), and celiac disease (12), as well as various types of cancer (1)(2)(3)(13)(14)(15)(16)(17)].…”

Section: Introductionmentioning

confidence: 99%

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

et al. 2006

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Induction of transglutaminase 2 (TGase 2) by epidermal growth factor (EGF) in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of TGase 2 in the development of these tumor-related phenotypes remains to be elucidated, but it has been shown that expression of a dominant-negative form of TGase 2 reverses EGF-mediated chemoresistance in breast cancer cells. We examined several different breast cancer cell lines, representing both EGF receptor (EGFR)-positive and EGFR-negative breast cancers, and found that doxorubicin-resistant cells had a higher level of TGase 2 compared with doxorubicin-sensitive cells independent of the EGFR expression level. TGase 2 inhibition increased the chemosensitivity of drug-resistant cells, concomitant with a decrease in nuclear factor-KB (NF-KB) activity. Increasing the level of TGase 2 in drugsensitive cells by transient transfection reduced the level of inhibitory subunit A of NF-KB (IKBA) and increased NF-KB activity in these cells. Inhibition of TGase 2 in drug-resistant cells by RNA interference increased the levels of IKBA, and this correlated with a shift in the accumulation of NF-KB from the nucleus to the cytosol. We recently showed that TGase 2 activated NF-KB through polymerization and depletion of free IKBA during inflammation. Therefore, increased expression of TGase 2 and subsequent activation of NF-KB may contribute to drug resistance in breast cancer cells independently of EGF signaling. (Cancer Res 2006; 66(22): 10936-43)

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“…During the years, it became clear that the enzyme overexpression occurred during phases of embryonic cell regression in organogenesis (e.g. in the foot interdigital membranes), that this same process could appear during regression after experimental induction of tissue hypertrophy (as proved by Laszlo Fesus in the liver of animals treated in vivo with lead salts) (Fesus et al 1987) and that in all these instances the death of the cells took place by apoptosis (Fesus et al 1991(Fesus et al , 1996. This link between transglutaminase 2 and programmed cell death has deeply influenced all successive transglutaminase research, including manipulation of transglutaminase expression for therapeutic goals, as occurred in the treatment of certain forms of leukemia (typically the promyelocytic leukemia, in which two cycles of treatment are effective in healing definitively over 85% of the patients) (Benedetti et al 1996;Ozpolat et al 2001;Asou 2007).…”

Section: The Years Of the Genementioning

confidence: 99%

An overview of the first 50 years of transglutaminase research

2008

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Induction and activation of tissue transglutaminase during programmed cell death

Cited by 449 publications

References 25 publications

Tissue Transglutaminase Protects against Apoptosis by Modifying the Tumor Suppressor Protein p110 Rb

Tissue Transglutaminase Protects against Apoptosis by Modifying the Tumor Suppressor Protein p110 Rb

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

An overview of the first 50 years of transglutaminase research

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