title: ECRG4 is a negative regulator of caspase-8-mediated apoptosis in human T-leukemia cells.
abstract: We previously established Fas-resistant variant clones from the human T-cell leukemia lines Jurkat and SUP-T13. Comparative gene expression analysis of the Fas-resistant and Fas-sensitive clones revealed several genes that were aberrantly expressed in the Fas-resistant clones. One of the genes, esophageal cancer-related gene 4 (ECRG4), contained a VDAC2-like domain that might be associated with apoptotic signals. In the present study, we examined the subcellular localization and function of ECRG4 in Fas-mediated apoptosis. By confocal fluorescence microscopy, ECRG4-EGFP fusion protein was detected in mitochondria, endoplasmic reticulum and the Golgi apparatus in gene-transfected HeLa cells. Overexpression of ECRG4 in Fas-sensitive Jurkat cells inhibited mitochondrial membrane permeability transition, leading to resistance against Fas-induced apoptosis. Tumor necrosis factor-alpha-induced apoptosis was also suppressed in ECRG4-overexpressing Jurkat cells. Immunoprecipitation assay demonstrated that ECRG4 is associated with procaspase-8. The inhibitory mechanism included the inhibition of caspase-8 activity and Bid cleavage. Since ECRG4 expression is downregulated in activated T cells, our results suggest that ECRG4 is a novel antiapoptotic gene which is involved in the negative regulation of caspase-8-mediated apoptosis in T cells.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsuzaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kamiguchi
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tamura
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tsukahara
authors.forename: Terufumi
authors.initials: T
authors.lastname: Kubo
authors.forename: Akari
authors.initials: A
authors.lastname: Takahashi
authors.forename: Emiri
authors.initials: E
authors.lastname: Nakazawa
authors.forename: Eri
authors.initials: E
authors.lastname: Saka
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yasuda
authors.forename: Shuji
authors.initials: S
authors.lastname: Takahashi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000235:genetics; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C476999:ECRG4 protein, human; D053200:Fas-Associated Death Domain Protein; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D053181:Caspase 8