| Title | Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | Billot, K, Coquil, C, Villiers, B, Josselin-Foll, B, Desban, N, Delehouze, C, Oumata, N, Le Meur, Y, Boletta, A, Weimbs, T, Grosch, M, Witzgall, R, Saunier, S, Fischer, E, Pontoglio, M, Fautrel, A, Mrug, M, Wallace, DPaul, Tran, PV, Trudel, M, Bukanov, NO, Ibraghimov-Beskrovnaya, O, Meijer, L |
| Journal | Am J Physiol Renal Physiol |
| Volume | 315 |
| Pagination | F57–F73 |
| Date Published | 2018 Mar 14 |
| ISSN | 1522-1466 |
| Abstract | Following the discovery of (R)-roscovitine's beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors are investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analogue (S)-CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1ε 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 CK1α isoforms is observed in all PKD mouse models. Further, the catalytic activities of both CK1ε and CK1α are increased in mouse polycystic kidneys. Inhibition of CK1ε and CK1α 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. |
| DOI | 10.1152/ajprenal.00489.2017 |
| Alternate Journal | Am. J. Physiol. Renal Physiol. |
| PubMed ID | 29537311 |
| Grant List | R01 DK103033 / DK / NIDDK NIH HHS / United States |
