title: Molecular mechanism by which acyclic retinoid induces nuclear localization of transglutaminase 2 in human hepatocellular carcinoma cells.
abstract: Nuclear accumulation of transglutaminase 2 (TG2) is an important step in TG2-dependent cell death. However, the underlying molecular mechanisms for nuclear translocation of TG2 are still poorly understood. In this study, we demonstrated that acyclic retinoid (ACR) induced nuclear accumulation of TG2 in JHH-7 cells, a hepatocellular carcinoma (HCC) leading to their apoptosis. We further demonstrated molecular mechanism in nuclear-cytoplasmic trafficking of TG2 and an effect of ACR on it. We identified a novel 14-amino acid nuclear localization signal (NLS) (466)AEKEETGMAMRIRV(479) in the 'C' domain and a leucine-rich nuclear export signal (NES) (657)LHMGLHKL(664) in the 'D' domain that allowed TG2 to shuttle between the nuclear and cytosolic milieu. Increased nuclear import of GAPDH myc-HIS fused with the identified NLS was observed, confirming its nuclear import ability. Leptomycin B, an inhibitor of exportin-1 as well as point mutation of all leucine residues to glutamine residues in the NES of TG2 demolished its nuclear export. TG2 formed a trimeric complex with importin-α and importin-β independently from transamidase activity which strongly suggested the involvement of a NLS-based translocation of TG2 to the nucleus. ACR accelerated the formation of the trimeric complex and that may be at least in part responsible for enhanced nuclear localization of TG2 in HCC cells treated with ACR.
authors.affiliation: Micro-Signaling Regulation Technology Unit, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies, Wako, Saitama, Japan.|Graduate School of Medical & Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Shrestha
authors.affiliation: Department of Basic Medicinal Science, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa Nagoya, Aichi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tatsukawa
authors.affiliation: Micro-Signaling Regulation Technology Unit, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies, Wako, Saitama, Japan.|Graduate School of Bioscience and Biotechnology, Department of Life Science, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Shrestha
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, KOWA Company, Ltd., Higashimurayama, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ishibashi
authors.affiliation: Department of Laboratory Medicine, The Jikei University School of Medicine, Nishi-shinbashi, Minato-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsuura
authors.affiliation: Graduate School of Medical & Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, Wako, Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kose
authors.affiliation: Department of Basic Medicinal Science, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa Nagoya, Aichi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hitomi
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, Wako, Saitama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Imamoto
authors.affiliation: Micro-Signaling Regulation Technology Unit, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies, Wako, Saitama, Japan.|Graduate School of Medical & Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.|Graduate School of Bioscience and Biotechnology, Department of Life Science, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kojima
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008969:Molecular Sequence Data; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D014212:Tretinoin; C034534:3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins