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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
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
-
Seven in Absentia Proteins
-
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
Substances
-
CDKN1A protein, human
-
Cyclin-Dependent Kinase Inhibitor p21
-
Homeodomain Proteins
-
JADE1 protein, human
-
Nuclear Proteins
-
TRPP Cation Channels
-
Transcription Factors
-
Tumor Suppressor Proteins
-
beta Catenin
-
polycystic kidney disease 1 protein
-
Ubiquitin-Protein Ligases
-
Von Hippel-Lindau Tumor Suppressor Protein
-
Seven in Absentia Proteins
-
Proteasome Endopeptidase Complex
-
VHL protein, human