Abstract
Glycogen synthase kinase 3β (GSK3β), 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), GSK3β expression is increased and plays a pathophysiological role. The current studies aimed to determine the mechanism for the increased GSK3β expression in PKD and its significance to disease progression. In mouse models of PKD, increases in renal GSK3β corresponded with increases in renal cAMP levels and disease progression. In vivo and in vitro studies revealed that GSK3β is a cAMP-responsive gene, and elevated cAMP levels, as seen in PKD, can increase GSK3β expression. In normal mice, vasopressin signaling induced by water deprivation increased GSK3β expression, which decreased following rehydration. Examination of the GSK3β promoter revealed five potential binding sites for the transcription factor, cAMP response element binding protein (CREB). CREB was found to bind to GSK3β promoter and essential for cAMP-mediated regulation of GSK3β. Importantly, this regulation was demonstrated to be part of a feed-forward loop in which cAMP through CREB regulates GSK3β expression, and GSK3β in turn positively regulates cAMP generation. GSK3β 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 464-476 |
| Number of pages | 13 |
| Journal | Journal of Molecular Cell Biology |
| Volume | 8 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jan 1 2016 |
| Externally published | Yes |
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Keywords
- cAMP
- CREB
- GSK3β
- In vitro cystogenesis
- PKD
- PKD1-knockout
- Vasopressin
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cell Biology
Cite this
A cAMP and CREB-mediated feed-forward mechanism regulates GSK3β in polycystic kidney disease. / Kakade, Vijayakumar R.; Tao, Shixin; Rajagopal, Madhumitha; Zhou, Xia; Li, Xiaogang; Yu, Alan S.L.; Calvet, James P.; Pandey, Pankaj; Rao, Reena.
In: Journal of Molecular Cell Biology, Vol. 8, No. 6, 01.01.2016, p. 464-476.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A cAMP and CREB-mediated feed-forward mechanism regulates GSK3β in polycystic kidney disease
AU - Kakade, Vijayakumar R.
AU - Tao, Shixin
AU - Rajagopal, Madhumitha
AU - Zhou, Xia
AU - Li, Xiaogang
AU - Yu, Alan S.L.
AU - Calvet, James P.
AU - Pandey, Pankaj
AU - Rao, Reena
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Glycogen synthase kinase 3β (GSK3β), 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), GSK3β expression is increased and plays a pathophysiological role. The current studies aimed to determine the mechanism for the increased GSK3β expression in PKD and its significance to disease progression. In mouse models of PKD, increases in renal GSK3β corresponded with increases in renal cAMP levels and disease progression. In vivo and in vitro studies revealed that GSK3β is a cAMP-responsive gene, and elevated cAMP levels, as seen in PKD, can increase GSK3β expression. In normal mice, vasopressin signaling induced by water deprivation increased GSK3β expression, which decreased following rehydration. Examination of the GSK3β promoter revealed five potential binding sites for the transcription factor, cAMP response element binding protein (CREB). CREB was found to bind to GSK3β promoter and essential for cAMP-mediated regulation of GSK3β. Importantly, this regulation was demonstrated to be part of a feed-forward loop in which cAMP through CREB regulates GSK3β expression, and GSK3β in turn positively regulates cAMP generation. GSK3β 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.
AB - Glycogen synthase kinase 3β (GSK3β), 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), GSK3β expression is increased and plays a pathophysiological role. The current studies aimed to determine the mechanism for the increased GSK3β expression in PKD and its significance to disease progression. In mouse models of PKD, increases in renal GSK3β corresponded with increases in renal cAMP levels and disease progression. In vivo and in vitro studies revealed that GSK3β is a cAMP-responsive gene, and elevated cAMP levels, as seen in PKD, can increase GSK3β expression. In normal mice, vasopressin signaling induced by water deprivation increased GSK3β expression, which decreased following rehydration. Examination of the GSK3β promoter revealed five potential binding sites for the transcription factor, cAMP response element binding protein (CREB). CREB was found to bind to GSK3β promoter and essential for cAMP-mediated regulation of GSK3β. Importantly, this regulation was demonstrated to be part of a feed-forward loop in which cAMP through CREB regulates GSK3β expression, and GSK3β in turn positively regulates cAMP generation. GSK3β 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.
KW - cAMP
KW - CREB
KW - GSK3β
KW - In vitro cystogenesis
KW - PKD
KW - PKD1-knockout
KW - Vasopressin
UR - http://www.scopus.com/inward/record.url?scp=85014511577&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014511577&partnerID=8YFLogxK
U2 - 10.1093/jmcb/mjw022
DO - 10.1093/jmcb/mjw022
M3 - Article
VL - 8
SP - 464
EP - 476
JO - Journal of Molecular Cell Biology
JF - Journal of Molecular Cell Biology
SN - 1674-2788
IS - 6
ER -