title: Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1.
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.
authors.affiliation: Renal Section, Boston University Medical Center, Boston, MA 02118, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Foy
authors.forename: Vipul C
authors.initials: VC
authors.lastname: Chitalia
authors.forename: Maria V
authors.initials: MV
authors.lastname: Panchenko
authors.forename: Liling
authors.initials: L
authors.lastname: Zeng
authors.forename: Delia
authors.initials: D
authors.lastname: Lopez
authors.forename: Jean W
authors.initials: JW
authors.lastname: Lee
authors.forename: Shaunak V
authors.initials: SV
authors.lastname: Rana
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boletta
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Leonidas
authors.initials: L
authors.lastname: Tsiokas
authors.forename: Klaus B
authors.initials: KB
authors.lastname: Piontek
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Germino
authors.forename: Mina I
authors.initials: MI
authors.lastname: Zhou
authors.forename: Herbert T
authors.initials: HT
authors.lastname: Cohen
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006207:Half-Life; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000473:pathology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D050396:TRPP Cation Channels; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051176:beta Catenin; D000098563:Seven in Absentia Proteins; C493956:CDKN1A protein, human; C469360:JADE1 protein, human; C497446:VHL protein, human