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Registration Number

0220U104728, 0115U003745 , R & D reports

Title

Structural and functional organization of mTOR / S6K-dependent signaling cascade in normal and malignant cells: a plurality mTOR and S6K kinases spliced isoforms

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Head

Filonenko Valeriy V., Доктор біологічних наук

Registration Date

26-12-2020

Organization

Institute of Molecular Biology and Genetics of NAS of Ukraine

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 At least two non-classical splicing mechanisms have been proposed, the formation of mTOR isoforms that lack or, conversely, contain a native catalytic domain of kinase and therefore can perform important regulatory functions. The first mechanism is transcriptional slippage, and the other is endonuclease excision of the deletion site at the level of spliced mRNA in the cytoplasm. Two new isoforms of the ribosomal protein kinase S6 (S6K1) - p55 and p60, which have a catalytic domain and lack the C- and N-terminal regulatory domain, respectively, have been identified and characterized. Molecular mechanisms of their formation are offered. Using the genomic editing system, cell lines with edited expression of known and newly identified S6K1 isoforms were created. Using these lines, their functional activity in the cell was studied. It was found that in contrast to the classical p70 and p85 isoforms, the new ones are constitutively active and their activity does not depend on the activity of mTOR. It was found that the expression of exclusively p60 isoform leads to epithelial-mesenchymal transition, and therefore it is an important link in the invasion and metastasis of malignant cells. Tissue-specific expression was established. Peculiarities of subcellular localization of mTOR and S6K1 isoforms and character of formed protein complexes are analyzed. A new type of posttranslational modification of proteins with the participation of coenzyme A - Coalition has been identified. Co-alluvium has been shown to be a new mechanism for protecting proteins from oxidation and degradation under oxidative or metabolic stress, and a new mechanism for regulating enzyme activity.

Product Description

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Garifulin Oleg M.
Krups'ka Iryna V.
Malanchuk Oksana M.
Pogribna Alla P.
Savins'ka Lilliya O.
Skorohod Oleksandr M.
Tyhonkova Iryna O.
Khoruzenko Antonina I.
Yakovenko Ludmyla F.

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2020-12-26