Billot, Katy and Coquil, Charlene and Villiers, Benoit and Josselin-Foll, Beatrice and Desban, Nathalie and Dekhouze, Claire and Oumata, Nassima and Le Meur, Yannick and Boletta, Alessandra and Weimbs, Thomas and Grosch, Melanie and Witzgall, Ralph and Saunier, Sophie and Fischer, Evelyne and Pontoglio, Marco and Fautrel, Alain and Mrug, Michal and Wallace, Darren and Tran, Pamela and Trudel, Marie and Bukanov, Nikolay and Ibraghimov-Beskrovnaya, Oxana and Meijer, Laurent (2018) Casein kinase 1 epsilon and 1 alpha as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 315 (1). F57-F73. ISSN 1931-857X, 1522-1466
Full text not available from this repository. (Request a copy)Abstract
Following the discovery of (R)-roscovitine's beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors have been investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analog (S)-CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1 epsilon expression at the mRNA and protein levels is enhanced in polycystic kidneys of 11 different PKD mouse models as well as in human polycystic kidneys. A shift in the pattern of CK1 alpha isoforms is observed in all PKD mouse models. Furthermore, the catalytic activities of both CK1 epsilon and CK1 alpha are increased in mouse polycystic kidneys. Inhibition of CK1 epsilon and CK1 alpha may thus contribute to the long-lasting attenuating effects of roscovitine and (S)-CR8 on cyst development. CDKs and CK1s may constitute a dual therapeutic target to develop kinase inhibitory PKD drug candidates.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CYCLIN-DEPENDENT KINASE; GLYCOGEN-SYNTHASE KINASE-3; CELL-CYCLE; C-MYC; AFFINITY-CHROMATOGRAPHY; PRIMARY CILIA; IN-VIVO; CISPLATIN CYTOTOXICITY; THERAPEUTIC TARGETS; CUBITUS INTERRUPTUS; casein kinase 1; cyclin-dependent kinase; kinase inhibitor; polycystic kidney disease; roscovitine |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Anatomie Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie > Prof. Dr. Ralph Witzgall |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Mar 2020 08:15 |
| Last Modified: | 06 Mar 2020 08:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14317 |
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