Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1

Rebecca L. Foy, Vipul C. Chitalia, Maria V. Panchenko, Liling Zeng, Delia Lopez, Jean W. Lee, Shaunak V. Rana, Alessandra Boletta, Feng Qian, Leonidas Tsiokas, Klaus B. Piontek, Gregory G. Germino, Mina I. Zhou, Herbert T. Cohen

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numberdds391
Pages (from-to)5456-5471
Number of pages16
JournalHuman Molecular Genetics
Volume21
Issue number26
DOIs
Publication statusPublished - Dec 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Foy, R. L., Chitalia, V. C., Panchenko, M. V., Zeng, L., Lopez, D., Lee, J. W., Rana, S. V., Boletta, A., Qian, F., Tsiokas, L., Piontek, K. B., Germino, G. G., Zhou, M. I., & Cohen, H. T. (2012). Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1. Human Molecular Genetics, 21(26), 5456-5471. [dds391]. https://doi.org/10.1093/hmg/dds391