Article

Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of gamma-glutamyl transpeptidase-dependent H2O2 production and S-thiolation.

Institute of General Pathology, University of Siena, Italy.
Free Radical Biology and Medicine (Impact Factor: 5.71). 10/1999; 27(5-6):623-35. DOI: 10.1016/S0891-5849(99)00111-2
Source: PubMed

ABSTRACT The expression of gamma-glutamyl transpeptidase (GGT), a plasma membrane ectoenzyme involved in the metabolism of extracellular reduced glutathione (GSH), is a marker of neoplastic progression in several experimental models, and occurs in a number of human malignant neoplasms and their metastases. Because it favors the supply of precursors for the synthesis of GSH, GGT expression has been interpreted as a member in cellular antioxidant defense systems. However, thiol metabolites generated at the cell surface during GGT activity can induce prooxidant reactions, leading to production of free radical oxidant species. The present study was designed to characterize the prooxidant reactions occurring during GGT ectoactivity, and their possible effects on the thiol redox status of proteins of the cell surface. Results indicate that: (i) in U937 cells, expressing significant amounts of membrane-bound GGT, GGT-mediated metabolism of GSH is coupled with the extracellular production of hydrogen peroxide; (ii) GGT activity also results in decreased levels of protein thiols at the cell surface; (iii) GGT-dependent decrease in protein thiols is due to sulfhydryl oxidation and protein S-thiolation reactions; and (iv) GGT irreversible inhibition by acivicin is sufficient to produce an increase of protein thiols at the cell surface. Membrane receptors and transcription factors have been shown to possess critical thiols involved in the transduction of proliferative signals. Furthermore, it was suggested that S-thiolation of cellular proteins may represent a mechanism for protection of vulnerable thiols against irreversible damage by prooxidant agents. Thus, the findings reported here provide additional explanations for the envisaged role played by membrane-bound GGT activity in the proliferative attitude of malignant cells and their resistance to prooxidant drugs and radiation therapy.

1 Bookmark
 · 
77 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: zet Gama glutamil transferaz birbirine benzemeyen iki alt üniteden oluşmuş bir hücre yüzey glikoproteinidir. Serumdaki gama glutamil transferaz'ın en önemli kaynağı karaciğerdir ve böbrek tubülleri, safra epiteli ve beyin kapillerinde yüksek miktarda sentez edilir. Gama glutamil transferaz safra yoluyla ilişkili hastalıkların teşhisinde kullanılan çok önemli bir tanısal testtir. Hücrede gama glutamil transferaz'ın asıl görevi hücre dışında bulunan indirgenmiş glutatyonu yıkmak ve hücre içi glutatyon sentezi için öncül aminoasitleri temin etmektir. Bununla birlikte, gama glutamil transferaz antioksidan/anti-toksik savunma ve hücresel proliferasyon/apopitozis dengesi gibi önemli indirgeyici olayların düzenlenmesine aracılık eden önemli bir enzimdir. Son deneysel çalışmalarda hücresel gama glutamil transferaz'ın demir ve diğer geçiş metallerinin varlığında reaktif oksijen türlerinin oluşumunu artırabileceği bildirilmiştir. Serum gama glutamil transferaz aktivitesindeki artış ve günümüzde önemli ölüm ve sakatlıklara yol açan koroner kalp hastalığı, kanser, diabetes mellitus ve inme gibi hastalıklar arasındaki ilişkiyi araştıran çok sayıda çalışma vardır. Kanser hücrelerinin kemoterapötik ilaçlara direnciyle GGT aktivitesinin artışı arasında bir ilişki olduğu da bildirilmektedir. Bu derlemede gama glutamil transferaz'ın klinik kullanım alanları, fizyolojik rolü ve epidemiyolojik çalışma sonuçlarıyla ilgili bilgilerin özetlenmesi amaçlanmıştır. Anahtar kelimeler: Gama glutamil transferaz, kanser, kardiyovasküler hastalıklar diabetes mellitus Gama glutamil transferaz (GGT) (EC 2.3.2.2) veya diğer bilinen ismiyle gama glutamil transpeptidaz (gluta-mine:D-glutamyl-peptide 5-glutamyltransferase) serumda ve birçok hücrenin dış yüzeyinde bulunan ve aminoasit veya küçük peptidlerin gama glutamil artıklarının transferini kataliz eden bir enzimdir (1). Dokulardan elde edilen GGT moleküler ağırlık ve yüküne bağlı olarak önemli farklılıklar göstermektedir. Dolayısıyla GGT izoenzimleri de serum ve dokuya bağlı olarak birbirinden farklılık göstermektedir. Moleküler ağırlığı 68000 Dalton olan bir glikoprotein yapısındadır ve birbirine benzemeyen iki alt üniteden oluşmuştur. GGT esas olarak yüksek miktarda salgılama ve emilim kapasitesine sahip (safra kanalı, karaciğer kanalikülleri, proksimal böbrek tubülleri, pankreas asiner hücreleri, pankreas duktulleri ve ince barsak fırça kenar hücreleri) hücre
    12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular diseases are threatening human health with rising morbidity and mortality rates. Gamma-glutamyltransferase (GGT) has been found to be involved in the pathogenesis of cardiovascular diseases, especially coronary artery disease, and the prognosis of cardiovascular disease may be predicted by increasing GGT levels. GGT levels are related to cardiovascular emergencies of chronic heart failure, and an elevated GGT level has been shown to be an independent predictive maker for cardiac death and cardiac transplantation. Investigation of the role of GGT in the mechanism of cardiac diseases will be helpful in developing preventive strategies and treatment methods.
    Experimental and clinical cardiology 01/2013; 18(1):53-56. · 0.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of gastrointestinal diseases has been found to be associated with Helicobacter pylori (H. pylori) infection and various biochemical stresses in stomach and intestine. These stresses, such as oxidative, osmotic and acid stresses, may bring about bi-directional effects on both hosts and H. pylori, leading to changes of protein expression in their proteomes. Therefore, proteins differentially expressed in H. pylori under various stresses not only reflect gastrointestinal environment but also provide useful biomarkers for disease diagnosis and prognosis. In this regard, proteomic technology is an ideal tool to identify potential biomarkers as it can systematically monitor proteins and protein variation on a large scale of cell's translational landscape, permitting in-depth analyses of host and pathogen interactions. By performing two-dimensional polyacrylamide gel electrophoresis (2-DE) followed by liquid chromatography-nanoESI-mass spectrometry (nanoLC-MS/MS), we have successfully pinpointed alkylhydroperoxide reductase (AhpC), neutrophil-activating protein and non-heme iron-binding ferritin as three prospective biomarkers showing up-regulation in H. pylori under oxidative, osmotic and acid stresses, respectively. Further biochemical characterization reveals that various environmental stresses can induce protein structure change and functional conversion in the identified biomarkers. Especially salient is the antioxidant enzyme AhpC, an abundant antioxidant protein present in H. pylori. It switches from a peroxide reductase of low-molecular-weight (LMW) oligomers to a molecular chaperone of high-molecular-weight (HMW) complexes under oxidative stress. Different seropositivy responses against LMW or HMW AhpC in H. pylori-infected patients faithfully match the disease progression from disease-free healthy persons to patients with gastric ulcer and cancer. These results has established AhpC of H. pylori as a promising diagnostic marker for gastrointestinal maladies, and highlight the utility of clinical proteomics for identifying disease biomarkers that can be uniquely applied to disease-oriented translational medicine.
    World Journal of Gastroenterology 02/2014; 20(6):1529-1536. · 2.43 Impact Factor

Full-text (3 Sources)

Download
83 Downloads
Available from
Nov 14, 2014

View other sources