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• W2143711252 abstract "Autosomal-dominant polycystic kidney disease (ADPKD) and von Hippel-Lindau (VHL) disease lead to large kidney cysts that share pathogenetic features. The polycystin-1 (PC1) and pVHL proteins may therefore participate in the same key signaling pathways. Jade-1 is a pro-apoptotic and growth suppressive ubiquitin ligase for beta-catenin and transcriptional coactivator associated with histone acetyltransferase activity that is stabilized by pVHL in a manner that correlates with risk of VHL renal disease. Thus, a relationship between Jade-1 and PC1 was sought. Full-length PC1 bound, stabilized and colocalized with Jade-1 and inhibited Jade-1 ubiquitination. In contrast, the cytoplasmic tail or the naturally occurring C-terminal fragment of PC1 (PC1-CTF) promoted Jade-1 ubiquitination and degradation, suggesting a dominant-negative mechanism. ADPKD-associated PC1 mutants failed to regulate Jade-1, indicating a potential disease link. Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1. By controlling Jade-1 abundance, PC1 and the PC1-CTF differentially regulate Jade-1-mediated transcriptional activity. A key target of PC1, the cyclin-dependent kinase inhibitor p21, is also up-regulated by Jade-1. Through Jade-1, PC1 and PC1 cleaved forms may exert fine control of beta-catenin and canonical Wnt signaling, a critical pathway in cystic renal disease. Thus, Jade-1 is a transcription factor and ubiquitin ligase whose activity is regulated by PC1 in a manner that is physiologic and may correlate with disease. Jade-1 may be an important therapeutic target in renal cystogenesis." @default.
• W2143711252 created "2016-06-24" @default.
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• W2143711252 date "2012-09-21" @default.
• W2143711252 modified "2023-09-23" @default.
• W2143711252 title "Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1" @default.
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• W2143711252 doi "https://doi.org/10.1093/hmg/dds391" @default.
• W2143711252 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3516131" @default.
• W2143711252 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23001567" @default.
• W2143711252 hasPublicationYear "2012" @default.
• W2143711252 type Work @default.

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