PMID:23001567

Citation	Foy, RL, Chitalia, VC, Panchenko, MV, Zeng, L, Lopez, D, Lee, JW, Rana, SV, Boletta, A, Qian, F, Tsiokas, L, Piontek, KB, Germino, GG, Zhou, MI and Cohen, HT (2012) Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1. Hum. Mol. Genet. 21:5456-71
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.
Links	PubMed PMC3516131 Online version:10.1093/hmg/dds391
Keywords	Amino Acid Sequence; Apoptosis; Cyclin-Dependent Kinase Inhibitor p21/genetics; Cyclin-Dependent Kinase Inhibitor p21/metabolism; Gene Expression Regulation; HEK293 Cells; Half-Life; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Humans; Kidney/cytology; Kidney/pathology; Molecular Sequence Data; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Polycystic Kidney, Autosomal Dominant/genetics; Polycystic Kidney, Autosomal Dominant/pathology; Proteasome Endopeptidase Complex/metabolism; TRPP Cation Channels/genetics; TRPP Cation Channels/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitination; Up-Regulation; Von Hippel-Lindau Tumor Suppressor Protein/genetics; Von Hippel-Lindau Tumor Suppressor Protein/metabolism; Wnt Signaling Pathway; beta Catenin/genetics; beta Catenin/metabolism; von Hippel-Lindau Disease/genetics; von Hippel-Lindau Disease/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:PKD1	involved_in	GO:0061136: regulation of proteasomal protein catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:1857562	P		Seeded From UniProt	complete
HUMAN:PKD1	located_in	GO:0005886: plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:PKD1	acts_upstream_of_or_within	GO:0061136: regulation of proteasomal protein catabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:JADE1	enables	GO:0003713: transcription coactivator activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:JADE1	located_in	GO:0005886: plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:JADE1	acts_upstream_of_or_within	GO:2000134: negative regulation of G1/S transition of mitotic cell cycle	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SIAH1	acts_upstream_of_or_within	GO:0006511: ubiquitin-dependent protein catabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SIAH1	enables	GO:0061630: ubiquitin protein ligase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:PKD1	involved_in	GO:0061136: regulation of proteasomal protein catabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PKD1	part_of	GO:0005886: plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:PKD1	acts_upstream_of_or_within	GO:0061136: regulation of proteasomal protein catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:1857562	P		Seeded From UniProt	complete

References

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