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.
Subject(s)
Biomarkers, Tumor/biosynthesis , Glioblastoma/genetics , Protein Kinase C-alpha/genetics , tRNA Methyltransferases/biosynthesis , Apoptosis/genetics , Biomarkers, Tumor/genetics , Carcinogenesis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Glioblastoma/pathology , Humans , Methionine/genetics , Protein Kinase C-alpha/biosynthesis , RNA, Transfer/genetics , tRNA Methyltransferases/geneticsABSTRACT
New technologies, which constantly become available for mutation detection and gene analysis, have contributed to an exponential rate of discovery of disease genes and variation in the human genome. The task of collecting and documenting this enormous amount of data in genetic databases represents a major challenge for the future of biological and medical science. The Locus Specific Databases (LSDBs) are so far the most efficient mutation databases. This review presents the main types of databases available for the analysis of mutations responsible for genetic disorders, as well as open perspectives for new therapeutic research or challenges for future medicine. Accurate and exhaustive collection of variations in human genomes will be crucial for research and personalized delivery of healthcare.
Subject(s)
Databases, Genetic , Genetic Diseases, Inborn/genetics , Mutation , Rare Diseases/genetics , Codon, Terminator , Ethnicity/genetics , Forecasting , Genetic Diseases, Inborn/classification , Genetic Diseases, Inborn/therapy , Genetic Therapy , Genetics, Medical/ethics , Genotype , Humans , Internet , Phenotype , RNA, Antisense/therapeutic use , Rare Diseases/classification , Rare Diseases/therapy , Terminology as Topic , Transcription, Genetic/drug effectsABSTRACT
A case of popliteal artery entrapment syndrome (PAES) is reported. A non smoker, 63-year-old man, consulted for severe claudication of the lower limb, with a sudden onset. There was no past history of vascular disease. Neither the arteriography nor the arterial doppler led to definite diagnosis. In our case, only the C.T. scan was contributive to the diagnosis. The age, 63, at which this abnormality became symptomatic, the abrupt appearance of ischaemic symptoms and the embryologic type of the arterial stenosis were particular. The surgical management was the only therapeutic option.
