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TAZ/Wnt-β-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease
TAZ/Wnt-β-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2020
- Publisher :
- Proceedings of the National Academy of Sciences, 2020.
-
Abstract
- Significance Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. There are few cures for ADPKD, although many researchers are trying to find a cure. The Hippo signaling pathway regulates organ growth and cell proliferation. Transcriptional coactivator with PDZ-binding motif (TAZ) is a Hippo signaling effector. In this study, we demonstrated that the PKD1–TAZ–Wnt–β-catenin–c-MYC signaling axis plays a critical role in cystogenesis. Endo IWR1 treatment, which inhibited β-catenin activity via AXIN stabilization, reduced cyst growth in an ADPKD model. Our findings provide a potential therapeutic target against ADPKD and would be important for clinical translation.<br />Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated β-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing β-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with β-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1–TAZ–Wnt–β-catenin–c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.
- Subjects :
- TAZ
0301 basic medicine
TRPP Cation Channels
Medical Sciences
Biology
Kidney
urologic and male genital diseases
Proto-Oncogene Proteins c-myc
Mice
03 medical and health sciences
0302 clinical medicine
Axin Protein
c-myc
AXIN1
Polycystic kidney disease
medicine
Animals
Humans
Wnt Signaling Pathway
Protein Kinase C
beta Catenin
Adaptor Proteins, Signal Transducing
Cell Proliferation
Mice, Knockout
Polycystic Kidney Diseases
Hippo signaling pathway
Multidisciplinary
PKD1
urogenital system
Cell growth
Wnt signaling pathway
Epithelial Cells
Biological Sciences
Polycystic Kidney, Autosomal Dominant
medicine.disease
female genital diseases and pregnancy complications
Cell biology
Disease Models, Animal
030104 developmental biology
polycystic kidney
Hippo signaling
030220 oncology & carcinogenesis
Catenin
Trans-Activators
Transcriptome
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 117
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....02aed9f672ab7230ee18e53a8137299f
- Full Text :
- https://doi.org/10.1073/pnas.2009334117