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La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1).
Fonseca, Bruno D; Zakaria, Chadi; Jia, Jian-Jun; Graber, Tyson E; Svitkin, Yuri; Tahmasebi, Soroush; Healy, Danielle; Hoang, Huy-Dung; Jensen, Jacob M; Diao, Ilo T; Lussier, Alexandre; Dajadian, Christopher; Padmanabhan, Niranjan; Wang, Walter; Matta-Camacho, Edna; Hearnden, Jaclyn; Smith, Ewan M; Tsukumo, Yoshinori; Yanagiya, Akiko; Morita, Masahiro; Petroulakis, Emmanuel; González, Jose L; Hernández, Greco; Alain, Tommy; Damgaard, Christian K.
Afiliación
  • Fonseca BD; From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada, brunodfonseca@gmail.com.
  • Zakaria C; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Jia JJ; From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
  • Graber TE; From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada, the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3,
  • Svitkin Y; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Tahmasebi S; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Healy D; From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
  • Hoang HD; From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
  • Jensen JM; the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
  • Diao IT; the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
  • Lussier A; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Dajadian C; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Padmanabhan N; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Wang W; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Matta-Camacho E; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Hearnden J; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Smith EM; the Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
  • Tsukumo Y; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Yanagiya A; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Morita M; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • Petroulakis E; the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada, Pfizer Canada Inc., Kirkland, Quebec H9J 2M5, Canada, and.
  • González JL; the Division of Basic Science, National Institute of Cancer, 22 San Fernando Ave., Tlalpan, Mexico City 14080, Mexico.
  • Hernández G; the Division of Basic Science, National Institute of Cancer, 22 San Fernando Ave., Tlalpan, Mexico City 14080, Mexico.
  • Alain T; From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada, tommy@arc.cheo.ca.
  • Damgaard CK; the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark, ckd@mbg.au.dk.
J Biol Chem ; 290(26): 15996-6020, 2015 Jun 26.
Article en En | MEDLINE | ID: mdl-25940091
The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5'TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ribonucleoproteínas / Autoantígenos / Biosíntesis de Proteínas / ARN Mensajero / Glicoproteínas de Membrana / Regulación hacia Abajo Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ribonucleoproteínas / Autoantígenos / Biosíntesis de Proteínas / ARN Mensajero / Glicoproteínas de Membrana / Regulación hacia Abajo Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos