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TAZ/Wnt-?-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease.


ABSTRACT: 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 ?-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing ?-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with ?-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1-TAZ-Wnt-?-catenin-c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.

SUBMITTER: Lee EJ 

PROVIDER: S-EPMC7682393 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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TAZ/Wnt-β-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease.

Lee Eun Ji EJ   Seo Eunjeong E   Kim Jin Won JW   Nam Sun Ah SA   Lee Jong Young JY   Jun Jaehee J   Oh Sumin S   Park Minah M   Jho Eek-Hoon EH   Yoo Kyung Hyun KH   Park Jong Hoon JH   Kim Yong Kyun YK  

Proceedings of the National Academy of Sciences of the United States of America 20201029 46


Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of <i>PKD1</i> or <i>PKD2</i>, 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 epithelia  ...[more]

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