期刊
JOURNAL OF MOLECULAR CELL BIOLOGY
卷 4, 期 6, 页码 398-408出版社
OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjs027
关键词
PKD; proximal tubules; bicaudal-C; cyclic AMP; PKA; PKI; miRNA
类别
资金
- American PKD Foundation [151a2r]
- Swiss National Science Foundation (Sinergia) [CRSI33_130662]
- Swiss National Science Foundation (SNF) [CRSI33_130662] Funding Source: Swiss National Science Foundation (SNF)
Genetic defects in autosomal-dominant polycystic kidney disease (ADPKD) promote cystic growth of renal tubules, at least in part by stimulating the accumulation of cAMP. How renal cAMP levels are regulated is incompletely understood. We show that cAMP and the expression of its synthetic enzyme adenylate cyclase-6 (AC6) are up-regulated in cystic kidneys of Bicc1(/) knockout mice. Bicc1, a protein comprising three K homology (KH) domains and a sterile alpha motif (SAM), is expressed in proximal tubules. The KH domains independently bind AC6 mRNA and recruit the miR-125a from Dicer, whereas the SAM domain enables silencing by Argonaute and TNRC6A/GW182. Bicc1 similarly induces silencing of the protein kinase inhibitor PKI by miR-27a. Thus, Bicc1 is needed on these target mRNAs for silencing by specific miRNAs. The repression of AC6 by Bicc1 might explain why cysts in ADPKD patients preferentially arise from distal tubules.
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