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M.Sc., Lomonosov Moscow State University - 2005
Thesis advisor: Alexey Ryazanov, Ph.D., D.Sc.
Graduate Program in Cellular and Molecular Pharmacology
RWJMS Research Tower
4th Floor Conference Room
Tuesday, April 15, 2014
TRPM7 is an essential and ubiquitous protein, comprising an ion channel and an alpha-kinase domain within one molecule. It plays an important role in maintaining cellular magnesium homeostasis, conducting magnesium ions into the cell. TRPM7 transcripts are among the most abundant in the cell. However protein levels are negligible, suggesting translational regulation of TRPM7 expression.
In this study we report that TRPM7 mRNA has evolutionary conserved two upstream open reading frames (uORFs) within its 5’-untranslated region (5’UTR). We analyzed the role of these uORFs in TRPM7 translational regulation. The uORFs have two major effects on the translation of the main coding sequence: (1) they drastically inhibit its translation in general and (2) they promote its optimal translation at reduced magnesium concentrations. Based on our results, we propose a mechanism of how these two uORFs affect magnesium sensitivity of the main coding sequence translation.
The phenomenon of post-transcriptional regulation of magnesium transporters/channels by magnesium levels is universal throughout the living forms and previously was shown to be the case for some prokaryotic and lower eukaryotic magnesium transporters. In this study we describe the first example of such regulation in a vertebrate. To our knowledge this is the first reported instance where translation of an ion channel is shown to be regulated by magnesium levels in higher eukaryotes.