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Oncogene. 2016 Apr 7;35(14):1785-96. doi: 10.1038/onc.2015.244. Epub 2015 Aug 3.

TRM6/61 connects PKCα with translational control through tRNAi(Met) stabilization: impact on tumorigenesis.

Author information

1
Department of Oncology, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.
2
INSERM, U1191, Montpellier, France.
3
Université de Montpellier, Montpellier, France.
4
Institut Curie, Centre de Recherche, Orsay, France.
5
CNRS UMR3348, Orsay, France.
6
University Paris-Sud XI, Orsay, France.
7
PSL Research University, Paris, France.
8
Department of Molecular Biology, Umeå University Umeå Sweden.
9
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
10
Laboratory of Oncogenetic, Institut Curie, Hopital René Huguenin, St-Cloud, France.
11
Laboratoire d'Informatique, de Robotique et de Microélectronique de Montpellier, Montpellier, France.
12
University of Bordeaux, Institut Européen de Chimie et Biologie, ARNA Laboratory, Pessac, France.
13
Laboratoire de Biologie Cellulaire et Moléculaire, Université Montpellier 1, Montpellier, France.
14
USR 3278, CNRS-UPHE-UPVD, CRIOBE, Moorea, French Polynesia.
15
Centre de Recherche de Biochimie Macromoléculaire, CNRS-UMR5237, Montpellier, France.
16
Department of Neurosurgery, Hôpital Gui de Chauliac, Montpellier, France.
17
Molecular Mechanisms of Tumor Progression Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.

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.

PMID:
26234676
DOI:
10.1038/onc.2015.244
[Indexed for MEDLINE]

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