title: TRM6/61 connects PKCα with translational control through tRNAi(Met) stabilization: impact on tumorigenesis.
abstract: Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C α (PKCα) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAi(Met)), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAi(Met). In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAi(Met)-overexpressing cells, PKCα overexpression decreased tRNAi(Met) expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAi(Met) expression with decreased expression of PKCα mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKCα tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: F
authors.initials: F
authors.lastname: Macari
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Y
authors.initials: Y
authors.lastname: El-Houfi
authors.affiliation: Institut Curie, Centre de Recherche, Orsay, France.|CNRS UMR3348, Orsay, France.|University Paris-Sud XI, Orsay, France.|PSL Research University, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Boldina
authors.affiliation: Department of Molecular Biology, Umeå University Umeå Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Khoury-Hanna
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: J
authors.initials: J
authors.lastname: Ollier
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: L
authors.initials: L
authors.lastname: Yazdani
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Laboratory of Oncogenetic, Institut Curie, Hopital René Huguenin, St-Cloud, France.
authors.forename: I
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: N
authors.initials: N
authors.lastname: Legrand
authors.affiliation: Laboratoire d'Informatique, de Robotique et de Microélectronique de Montpellier, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: Paulet
authors.affiliation: University of Bordeaux, Institut Européen de Chimie et Biologie, ARNA Laboratory, Pessac, France.
authors.forename: S
authors.initials: S
authors.lastname: Durrieu
authors.affiliation: Department of Molecular Biology, Umeå University Umeå Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Byström
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire, Université Montpellier 1, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Delbecq
authors.affiliation: USR 3278, CNRS-UPHE-UPVD, CRIOBE, Moorea, French Polynesia.|Centre de Recherche de Biochimie Macromoléculaire, CNRS-UMR5237, Montpellier, France.
authors.forename: B
authors.initials: B
authors.lastname: Lapeyre
authors.affiliation: Department of Neurosurgery, Hôpital Gui de Chauliac, Montpellier, France.
authors.forename: L
authors.initials: L
authors.lastname: Bauchet
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: J
authors.initials: J
authors.lastname: Pannequin
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.|Molecular Mechanisms of Tumor Progression Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Hollande
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Pan
authors.affiliation: University of Bordeaux, Institut Européen de Chimie et Biologie, ARNA Laboratory, Pessac, France.
authors.forename: M
authors.initials: M
authors.lastname: Teichmann
authors.affiliation: Institut Curie, Centre de Recherche, Orsay, France.|CNRS UMR3348, Orsay, France.|University Paris-Sud XI, Orsay, France.|PSL Research University, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Vagner
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: A
authors.initials: A
authors.lastname: David
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: A
authors.initials: A
authors.lastname: Choquet
authors.affiliation: Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.|INSERM, U1191, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: Joubert
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008715:Methionine / Q000235:genetics; D051571:Protein Kinase C-alpha / Q000096:biosynthesis / Q000235:genetics*; D012343:RNA, Transfer / Q000235:genetics; D012359:tRNA Methyltransferases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D012343:RNA, Transfer; D008715:Methionine; D012359:tRNA Methyltransferases; C000605775:TRMT61A protein, human; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha