γ ‐Glutamyl Transpeptidase and its Role in Melanogenesis: Redox Reactions and Regulation of Tyrosinase

Abstract

Metabolism of glutathione by gamma-glutamyl transpeptidase (gamma-GT) at the level of cell membrane has been shown to generate hydrogen peroxide in many cell types including human melanomas. gamma-GT does not appear to be involved in cysteine uptake for pheomelanin production in melanoma cells and does not contribute significantly to the pheomelanin synthesized in B16 melanoma cells. We have therefore examined the possibility of gamma-GT mediated production of prooxidant reactions and its effect, if any, on pigmentation using B16 melanoma cells. Our results indicate that in B16 melanoma cells, gamma-GT activity leads to the production of hydrogen peroxide. We further show that the nuclear levels of the redox sensitive transcription factor NF-kappa B is regulated by H2O2 formed by the action of gamma-GT: stimulation and inhibition of gamma-GT affect the levels of NF-kappa B. Tumor necrosis factor alpha, a hypopigmenting cytokine, known to activate NF-kappa B also up-regulates the gamma-GT messenger RNA and activity. Stimulation of gamma-GT generated prooxidant reactions led to a decrease in tyrosinase activity. We therefore propose that prooxidant reactions mediated by gamma-GT in turn regulate the levels of tyrosinase in pigment cells. Our findings thus introduce a new aspect in the regulation of pigmentation and ascribe a novel role for gamma-GT in pigment cells.

Insect immune resistance to parasitoids

“…It is of some interest to note that in response to oxidative stress, B16 melanoma cells produce a substantial amount of H 2 O 2 at the cell surface as a result of the actcivity of γ-glutamyl transpeptidase. γ -glutamyl transpeptidase-derived H 2 O 2 modulates the activity of the redox-sensitive transcription factor NF-κB, which leads to a down-regulation of tyrosinase activity and alteration in melanogeneic processes (Chaubal et al, 2002). Critically altered melanogenic processes also result from myeloperoxidase-mediated oxidation of tyrosine, which produces such potentially damaging molecules as the tyrosyl radical, tyrosine peroxide and dityrosine (Fig.…”

Production and utilization of hydrogen peroxide associated with melanogenesis and tyrosinase‐mediated oxidations of DOPA and dopamine

“…The role of H 2 O 2 in melanogenesis has not been clearly defined, with some reports indicating it functions to enhance pigment formation by regulating levels of tyrosinase [12], others suggesting the molecule serves as a potent inhibitor of tyrosinase [13]. The problem in attempting to identify and clarify peroxidative activity during melanogenesis is that past assessments frequently have been based in large part on reaction rates following exposure of cells to either exogenous H 2 O 2 [8,11], or to various reactive intermediates of oxygen followed by inhibition assays.…”

Biochemical characterization of a new melanoma model ??? the minipig MeLiM strain

“…2), explaining its black colour and high mechanical resistance. MeLiM tumours express all the typical melanoma enzyme activities -tyrosinase (the key enzyme of melanogenesis), AE-mannosidase [29,30] (involved in metastatic ability of melanoma cells [15]), and GGT [17] (thought to have a role in maintaining the intracellular glutathione level [31], in protection against oxidative stress [16,17] and in the regulation of tyrosinase level in pigment cells [18]). The decreased melanin concentration in devitalized tumours (Table 1), together with the extinction of tyrosinase activity (Fig.…”

“…This study involved a detailed biochemical characterization of the MeLiM tumours, including (i) melanin concentration and type; (ii) melanosomes concentration and type; (iii) melanoma enzymes, particularly tyrosinase, which represent three key parameters of melanoma differentiation [14]. In addition to tyrosinase, AE-mannosidase, which is known to participate in melanoma dissemination [15], and ª-glutamyltransferase, which is involved in the protection against oxidative stress [16,17] and in the regulation of the tyrosinase level in pigment cells [18], were also analysed. A comparison of biochemical data between native and devitalized tumours supports previous histological findings of the conversion of devitalized tumours into connective tissue [12].…”