Achacin induces cell death in HeLa cells through two different mechanisms

Kanzawa, Nobuyuki; Shintani, S.; Ohta, Kaoru; Kitajima, Seiji; Ehara, Tatsuya; Kobayashi, Hiroko; Kizaki, Harutoshi; Tsuchiya, Takahide

doi:10.1016/j.abb.2003.12.007

Cited by 34 publications

(33 citation statements)

References 27 publications

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“…Most of the previously described LAAO enzymes present proapoptotic effects that have been related to H 2 O 2 production. 8,26,27 We had no difficulties in developing stable cell lines with constitutive or inducible expression of active IL4I1 in HEK293 cells. While the enzyme is probably functionally active inside the cell, it is highly compartmentalized, restricted to vesicles ( Figure 3B and data not shown) where it is likely to be physically separated from its substrate, and hence metabolically inactive.…”

Section: Discussionmentioning

confidence: 99%

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

Boulland

Marquet

Molinier‐Frenkel

et al. 2007

Blood

159

177

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Interleukin-4-induced gene 1 (IL4I1) was first described as a B-cell IL4-inducible gene and is highly expressed in primary mediastinal B-cell lymphomas. We established stable HEK293 clones expressing human and mouse IL4I1 to examine their biochemical properties and function. Both proteins were secreted into the culture medium, and we observed the secretion of endogenous human IL4I1 (hIL4I1) protein in a mediastinal lymphoma B-cell line, MedB-1. We showed that IL4I1 has L-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine. Immunohistochemical analysis of secondary lymphoid organs showed staining of germinal center macrophages and inflammatory myeloid cells. In vitro, functional enzyme was highest in mature dendritic cells (DCs), suggesting a role in antigenpresenting cell/T-lymphocyte cross-talk. Indeed, hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4 ؉ and CD8 ؉ T cells. IntroductionInterleukin-4 (IL4) is the master cytokine for T-helper type 2 (Th2) lymphocyte differentiation and function. Along with its important role in B-lymphocyte stimulation by T-helper cells in germinal centers of secondary lymphoid organs, it also regulates the growth and function of many different cell types of the immune system. 1 IL4 transcriptional effects are primarily mediated by the signalization and transcription factor 6 (STAT6), which is responsible for the induction and repression of multiple target genes. 2 An immediate-early IL4-inducible gene called interleukin fourinduced gene 1 (FIG1/IL4I1) has first been described in the mouse 3 and subsequently characterized in human B cells. 4 IL4I1 mRNA expression is restricted to lymphoid tissues, with the highest levels found in lymph nodes and spleen. 4,5 IL4-activated murine B cells express IL4I1 within 2 hours of stimulation. We have demonstrated that high levels of expression of this gene are characteristic of primary mediastinal large B-cell lymphoma (PMBL), a specific subtype of diffuse large B-cell lymphoma. 5 The high expression of IL4I1 by PMBL may result from the constitutive activation of STAT6 in these tumors. 6 Both human and mouse IL4I1 mRNA sequences encode a protein containing a putative signal peptide indicative of potential secretion and a large central domain, highly homologous to flavin-containing amino acid oxidases. 3,4 While sharing high similarity over the majority of the sequence (547 amino acids of the 567 in the human sequence), the human and mouse proteins diverge substantially at their C-terminal region. 4 The IL4I1 protein shares the highest similarity with proteins presenting L-amino acid oxidase (LAAO) activity, such as snake venom LAAO,7,8 and mouse milk LAAO. 9 Recently, Mason et al have demonstrated that mouse IL4I1 (mIL4I1) possesses an LAAO activity toward aromatic amino acids. The enzyme was mostly active at acidic pH, in contrast to other known members of the LAAO family, and its expression was restricted primarily to lysosomes. 10 In this work, w...

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Section: Discussionmentioning

confidence: 99%

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

Boulland

Marquet

Molinier‐Frenkel

et al. 2007

Blood

159

177

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“…We have reported that the depletion of an essential amino acid can trigger apoptotic cell death in yeast (Eisler et al, 2004). Other members of the LAAO family, such as achacin from the body surface mucus of the giant African snail (Achatina fulica Ferussac) and the apoptosis-inducing protein (AIP) from parasiteinfected fish, deplete arginine, lysine, tryptophan and tyrosine, or only lysine, from mammalian cell culture medium (Kanzawa et al, 2004;Murakawa in the presence of catalase (1.5 µM) for 30 min. The cells were then washed three times with PBS and digested with proteinase K (0.2 mg/ml).…”

Section: Interaction Of Laao With the Yeast Cellmentioning

confidence: 99%

Induction of apoptosis in yeast by L‐amino acid oxidase from the Malayan pit viper Calloselasma rhodostoma

Ande

Fussi

Knauer

et al. 2008

Yeast

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Here we report for the first time that L-amino acid oxidase (LAAO), a major component of snake venom, induces apoptosis in yeast. The causative agent for induction of apoptosis has been shown to be hydrogen peroxide, produced by the enzymatic activity of LAAO. However, the addition of catalase, a specific hydrogen peroxide scavenger, does not prevent cell demise completely. Intriguingly, depletion of leucine from the medium by LAAO and the interaction of LAAO with yeast cells are shown to be the major factors responsible for cell demise in the presence of catalase.

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“…A plausible mechanism that may contribute to the apoptosisinducing effects of LAAO is the depletion of L-amino acids contained in the cell culture medium. Indeed, it has been reported that achacin from the body surface mucus of the giant African snail Achatina fulica Férussac [17] and apoptosis inducing protein (AIP) from parasite-infected fish [18] deplete media of specific amino acids, which may contribute to their toxicity. It is therefore important to determine whether the addition of LAAO and catalase to the culture medium under conditions that induce apoptosis also results in the consumption of specific essential amino acids.…”

Section: L-amino Acid Oxidase (Laao) Induces Different Modes Of Cell mentioning

confidence: 99%

“…On the other hand the apoptosisinducing activity of achacin and AIP have also been ascribed to the consumption of the amino acid substrates in the medium, e.g. Lys in the case of AIP [18] and aromatic and basic amino acids in the case of achacin [17]. A further factor that might play a crucial role in induction of cell death could be specific interactions of LAAO at the cell surface, as first suggested by Suhr and Kim [19].…”

Section: Introductionmentioning

confidence: 95%

“…It has been reported that L-amino acid oxidases (LAAOs), present in the venom of various snakes, such as crotalids, elapids and viperids, possess antibacterial properties [15] as well as an anti-HIV activity [16] and can induce cell death [17][18][19][20]. These enzymes are members of the well-studied family of flavin (FAD) dependent oxidases.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of cell death induction by L-amino acid oxidase, a major component of ophidian venom

et al. 2006

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L-amino acid oxidase (LAAO) from the Malayan pit viper induces both necrosis and apoptosis in Jurkat cells. Cell death by necrosis is attributed to H 2 O 2 produced by oxidation of α-amino acids. In the presence of catalase that effectively scavenges H 2 O 2, a switch to apoptosis is observed. The major factors contributing to apoptosis are proposed to be: (i) generation of toxic intermediates from fetal calf serum (ii) binding and internalization of LAAO. The latter process appears to be mediated by the glycan moiety of the enzyme as desialylation reduces cytotoxicity. D-amino acid oxidase (DAAO), which catalyzes the same reaction as LAAO but lacks glycosylation, triggers necrosis as a consequence of H 2 O 2 production but not apoptosis in the presence of catalase. Thus induction of cell death by LAAO appears to involve both the generation of H 2 O 2 and the molecular interaction of the glycan moiety of the enzyme with structures at the cell surface.S. R. Ande, P. R. Kommoju contributed equally to this work.

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Achacin induces cell death in HeLa cells through two different mechanisms

Cited by 34 publications

References 27 publications

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

Induction of apoptosis in yeast by L‐amino acid oxidase from the Malayan pit viper Calloselasma rhodostoma

Mechanisms of cell death induction by L-amino acid oxidase, a major component of ophidian venom

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