title: Zfat-deficient CD4⁺ CD8⁺ double-positive thymocytes are susceptible to apoptosis with deregulated activation of p38 and JNK.
abstract: Zfat, which is a nuclear protein harboring an AT-hook domain and 18-repeats of C2H2 zinc-finger motif, is highly expressed in immune-related tissues, including the thymus and spleen. T cell specific deletion of the Zfat gene by crossing Zfat(f/f) mice with LckCre mice yields a significant reduction in the number of CD4(+) CD8(+) double-positive (DP) thymocytes. However, physiological role for Zfat in T cell development in the thymus remains unknown. Here, we found that Zfat-deficient DP thymocytes in Zfat(f/f)-LckCre mice were susceptible to apoptosis both at an unstimulated state and in response to T cell receptor (TCR)-stimulation. The phosphorylation levels of p38 and JNK were elevated in Zfat-deficient thymocytes at an unstimulated state with an enhanced phosphorylation of ATF2 and with an over-expression of Gadd45α⋅ On the other hand, the activation of JNK in the Zfat-deficient thymocytes, but not p38, was strengthened and prolonged in response to TCR-stimulation. All these results demonstrate that Zfat critically participates in the development of DP thymocytes through regulating the activities of p38 and JNK.
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ishikura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Doi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Yuri
authors.initials: Y
authors.lastname: Iwaihara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Hideshima
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C529571:ZFAT protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: APOPTOSIS; JNK; THYMOCYTE; ZFAT; p38