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- Macari, F., et al.
(författare)
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TRM6/61 connects PKCα with translational control through tRNAiMet stabilization : impact on tumorigenesis
- 2016
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 35:14, s. 1785-1796
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Tidskriftsartikel (refereegranskat)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 [alpha] (PKC[alpha]) 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 (tRNAiMet), 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 tRNAiMet. 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/tRNAiMet-overexpressing cells, PKC[alpha] overexpression decreased tRNAiMet expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAiMet expression with decreased expression of PKC[alpha] 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 PKC[alpha] tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.
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| 2. |
- Baltanas, R., et al.
(författare)
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Pheromone-Induced Morphogenesis Improves Osmoadaptation Capacity by Activating the HOG MAPK Pathway
- 2013
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1937-9145 .- 1945-0877. ; 6:272
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Tidskriftsartikel (refereegranskat)abstract
- Environmental and internal conditions expose cells to a multiplicity of stimuli whose consequences are difficult to predict. We investigate the response to mating pheromone of yeast cells adapted to high osmolarity. Events downstream of pheromone binding involve two mitogen-activated protein kinase (MAPK) cascades: the pheromone response (PR) and the cell wall integrity (CWI) response. Although the PR MAPK pathway shares components with a third MAPK pathway, the high osmolarity (HOG) response, each one is normally only activated by its cognate stimulus, a phenomenon called insulation. We found that in cells adapted to high osmolarity, PR activated the HOG pathway in a pheromone- and osmolarity-dependent manner. Activation of HOG by the PR was not due to loss of insulation, but rather a response to a reduction in internal osmolarity, which resulted from an increase in glycerol release caused by the PR. By analyzing single-cell time courses, we found that stimulation of HOG occurred in discrete bursts that coincided with the "shmooing" morphogenetic process. Activation required the polarisome, the CWI MAPK Slt2, and the aquaglyceroporin Fps1. HOG activation resulted in high glycerol turnover, which improved adaptability to rapid changes in osmolarity. Our work shows how a differentiation signal can recruit a second, unrelated sensory pathway to fine-tune yeast response in a complex environment.
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