Transglutaminase may mediate certain physiological effects of endogenous amines and of amine-containing therapeutic agents

Russell, Diane Haddock; Womble, J. R.

doi:10.1016/0024-3205(82)90236-3

Cited by 27 publications

(7 citation statements)

References 56 publications

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“…Several effective cancer chemotherapeutic agents, including adriamycin, actinomycin D, mithramycin and bleomycin, have been shown to serve as substrates in TGase-catalyzed reactions (Russell and Womble, 1982). The ability of these agents to serve as TGase substrates is even more interesting when their reported K,,, values are compared with that of a physiological substrate such as putrescine.…”

Section: Discussionmentioning

confidence: 99%

“…However, the K, for putrescine incorporation into protein substrate was approximately 100 pM, whereas the K, for adriamycin was approx. 1 pM and for actinomycin D about 30 pM (Russell and Womble, 1982). These results suggested that, at relatively lower concentrations, incorporation of actinomycin D and adriamycin would be significant compared with that of endogenous amine substrates such as putrescine.…”

Section: Figure 4 -Localization Of Tgase In Mcf-7wt+adr Cells (A)mentioning

confidence: 99%

“…At this point we do not understand the significance of elevated TGase expression in adriamycin-resistant breast cancer cells. However, in view of the fact that adriamycin is the most active single agent currently used in clinical treatment of breast cancer, the observation of high levels of TGase expression in drug-resistant breast tumor cells in conjunction with earlier observations that adriamycin is a substrate for TGasecatalyzed cross-linking reactions (Russell and Womble, 1982) may have some important clinical implications in reversing drug resistance or prognostic importance in breast cancer.…”

Section: Figure 4 -Localization Of Tgase In Mcf-7wt+adr Cells (A)mentioning

confidence: 99%

“…TGase is also capable of catalyzing irreversible conjugation of several amines (such as polyamines) to glutamine residues of certain proteins (Davies et al, 1988). Several anti-cancer agents, including actinomycin D, adriamycin, mithramycin and bleomycin, have been shown to serve as amine substrates for TGase (Russell and Womble, 1982). It is possible that the efficacy of these drugs may relate closely to their ability to serve as substrates for TGase and to the presence of TGase activity in target cells.…”

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confidence: 99%

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High levels of transglutaminase expression in doxorubicin‐resistant human breast carcinoma cells

Mehta

1994

Intl Journal of Cancer

103

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Tissue type II transglutaminase (TGase) is a member of the TGase family that catalyzes Ca(2+)-dependent covalent cross-linking of several amines to the gamma-carboxamide group of protein-bound glutamine residues. The degree of therapeutic efficacy or toxicity of drugs may be related to their ability to serve as a substrate for TGase and their covalent linkage to glutamine residues of regulatory proteins through the catalytic action of this enzyme. Here, doxorubicin (adriamycin)-resistant human breast carcinoma MCF-7ADR cells exhibited 40- to 6C-fold higher TGase activity than control drug-sensitive MCF-7WT cells. The same was observed in vivo: a small proportion of tumor cells became positive for TGase after administration of adriamycin-based chemotherapy to patients with breast carcinoma. Similarly, continuous culture of MCF-7WT cells in the presence of adriamycin led to the appearance of the drug-resistant phenotype that was in turn associated with increased expression of TGase. This increase in TGase was specific for adriamycin resistance. Like most known TGase, MCF-7ADR TGase was completely dependent on the presence of Ca2+ for its catalytic activity. Based on its immunoreactivity, the TGase in MCF-7ADR cells was identified as an 85-kDa tissue-type TGase and was present only in the soluble form. Immunoblot analysis revealed that the increase in TGase activity was due to accumulation of the protein. Two cytosolic proteins of approximately 20 and 30 kDa in MCF-7 cells served as suitable acyl donor substrates in TGase-catalyzed reactions.

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Section: Discussionmentioning

confidence: 99%

Section: Figure 4 -Localization Of Tgase In Mcf-7wt+adr Cells (A)mentioning

confidence: 99%

Section: Figure 4 -Localization Of Tgase In Mcf-7wt+adr Cells (A)mentioning

confidence: 99%

mentioning

confidence: 99%

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High levels of transglutaminase expression in doxorubicin‐resistant human breast carcinoma cells

Mehta

1994

Intl Journal of Cancer

103

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“…Based on the information accumulated over the years about the possible connections of transglutaminase enzymes and drug-induced cytotoxic effects (Griffin et al, 1978;Russell and Womble, 1982;Piacentini et al, 1993;Han and Park, 1999a), important knowledge can be provided by studies clarifying the role of tTG on the molecular mechanisms of chemotherapeutic agents. Our results suggest, that although the induction of tTG is a frequent component of the apoptotic phenotype, it is pharmacologically dissociable from the early phase of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Separation of the Expression of Tissue Transglutaminase and Apoptosis after Chemotherapeutic Treatment of HepG2 Cells

2001

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Chemotherapeutic drugs are known to eliminate cancer cells by inducing apoptosis. Tissue transglutaminase (tTG), a frequent player in apoptotic processes, is markedly induced in drug-resistant cancer cells. To better understand the action of apoptosis-inducing drugs, our study elucidates changes in the expression of tTG in the early phase of cell death, before the downstream events of apoptosis. We demonstrate that HepG2 cells uniformly induce both tTG mRNA and enzyme activity upon treatment with cisplatin, doxorubicin, and bleomycin, chemotherapeutic agents with different modes of action. The expression of fas ligand, caspase3 and baxalpha changes differentially or remain unaffected. tTG expression did not change significantly after administration of either the peroxisome proliferator activated receptor-alpha agonist WY14643 or the retinoid X receptor-specific analog LG 100268. However, both compounds blocked drug-induced tTG induction without affecting the extent of cell death. The pleiotropic cytokine interleukin-6 effectively rescued hepatoma cells from apoptosis while tTG induction still took place, along with the induction of antiapoptotic transcripts bcl-x(L), gp130, and her2/neu. These results suggest that the induction of tTG, although present in drug-induced apoptosis, is pharmacologically dissociable from the early, initiating events of apoptosis. Blocking the induction of tTG during drug-induced cell death may alleviate limiting side effects of anticancer agents, including fibrosis and neuropathies.

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Rat gastrointestinal transglutaminase: Demonstration of enzyme activity and cell and tissue distributions

Patel

Bruce

Bjarnason

1985

Cell Biochemistry & Function

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The properties, tissue and cellular distribution of intestinal transglutaminase have been investigated. Transglutaminase was assayed with dimethylcasein and [14C]putrescine as substrates. The enzyme has maximum activity at pH 10, although more reliable assays are made at pH 9. Transglutaminase showed an absolute requirement for Ca2+ and exhibited linear assay kinetics. The Km for putrescine was approx. 0.15 mmol/l. Tissue distribution studies suggest transglutaminase is more active in the more muscular segments of the gut. The cellular localization in jejunum was investigated by sequential cell release techniques. Approximately 2 per cent of the total activity was found in the enterocytes and crypt cells. Most of the activity was in the submucosa and serosa suggesting an interstitial cell localization. Acute hypoplastic enteropathy induced by methotrexate was accompanied by a striking decrease in mucosal transglutaminase but the activity returned to control values by 72 h. There was no significant increase in activity during the period of intense crypt cell hyperplasia and it is concluded that intestinal transglutaminase is not implicated in crypt cell proliferation.

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Transglutaminase may mediate certain physiological effects of endogenous amines and of amine-containing therapeutic agents

Cited by 27 publications

References 56 publications

High levels of transglutaminase expression in doxorubicin‐resistant human breast carcinoma cells

High levels of transglutaminase expression in doxorubicin‐resistant human breast carcinoma cells

Pharmacological Separation of the Expression of Tissue Transglutaminase and Apoptosis after Chemotherapeutic Treatment of HepG2 Cells

Rat gastrointestinal transglutaminase: Demonstration of enzyme activity and cell and tissue distributions

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