| First Author | Kakade VR | Year | 2016 |
| Journal | J Mol Cell Biol | Volume | 8 |
| Issue | 6 | Pages | 464-476 |
| PubMed ID | 27190311 | Mgi Jnum | J:381389 |
| Mgi Id | MGI:6873501 | Doi | 10.1093/jmcb/mjw022 |
| Citation | Kakade VR, et al. (2016) A cAMP and CREB-mediated feed-forward mechanism regulates GSK3beta in polycystic kidney disease. J Mol Cell Biol 8(6):464-476 |
| abstractText | Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is commonly known to be regulated at the level of its activity. However, in some diseases including polycystic kidney disease (PKD), GSK3beta expression is increased and plays a pathophysiological role. The current studies aimed to determine the mechanism for the increased GSK3beta expression in PKD and its significance to disease progression. In mouse models of PKD, increases in renal GSK3beta corresponded with increases in renal cAMP levels and disease progression. In vivo and in vitro studies revealed that GSK3beta is a cAMP-responsive gene, and elevated cAMP levels, as seen in PKD, can increase GSK3beta expression. In normal mice, vasopressin signaling induced by water deprivation increased GSK3beta expression, which decreased following rehydration. Examination of the GSK3beta promoter revealed five potential binding sites for the transcription factor, cAMP response element binding protein (CREB). CREB was found to bind to GSK3beta promoter and essential for cAMP-mediated regulation of GSK3beta. Importantly, this regulation was demonstrated to be part of a feed-forward loop in which cAMP through CREB regulates GSK3beta expression, and GSK3beta in turn positively regulates cAMP generation. GSK3beta or CREB inhibition reduced transepithelial fluid secretion and cyst expansion in vitro Thus, disruption at any point of this destructive cycle may be therapeutically useful to reduce cyst expansion and preserve renal function in PKD. |
