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PMID:23001567

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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

Significance

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

Notes

See also

References

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