PUBLICATION

Polycystin-1, STAT6, and P100 Function in a Pathway that Transduces Ciliary Mechanosensation and Is Activated in Polycystic Kidney Disease

Authors
Low, S.H., Vasanth, S., Larson, C.H., Mukherjee, S., Sharma, N., Kinter, M.T., Kane, M.E., Obara, T., and Weimbs, T.
ID
ZDB-PUB-060124-3
Date
2006
Source
Developmental Cell   10(1): 57-69 (Journal)
Registered Authors
Obara, Tomoko
Keywords
none
MeSH Terms
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation/drug effects
  • Gene Expression Regulation/physiology
  • Blotting, Western/methods
  • Humans
  • Luciferases/metabolism
  • Cilia/drug effects
  • Cilia/metabolism*
  • Blotting, Northern/methods
  • Fluorescent Antibody Technique/methods
  • Cell Line
  • Molecular Biology/methods
  • STAT6 Transcription Factor/metabolism*
  • Embryo, Mammalian
  • Gene Expression/physiology
  • Protein Structure, Tertiary
  • Amino Acid Sequence
  • Immunoprecipitation/methods
  • Transfection/methods
  • Zebrafish
  • Interleukin-4/pharmacology
  • Epithelium/drug effects
  • Epithelium/metabolism
  • Embryo, Nonmammalian
  • Translocation, Genetic
  • TRPP Cation Channels
  • Kidney/metabolism
  • Kidney/pathology
  • Kidney/ultrastructure
  • Models, Biological
  • Trans-Activators/physiology
  • Mutagenesis/physiology
  • Proteins/physiology*
  • Animals
  • Nuclear Proteins/metabolism*
  • Enzyme Activation/physiology
  • Protein Binding
  • Mechanotransduction, Cellular/physiology*
  • Polycystic Kidney, Autosomal Dominant/metabolism*
  • Polycystic Kidney, Autosomal Dominant/pathology
PubMed
16399078 Full text @ Dev. Cell
Abstract
Primary cilia are implicated in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which results from defects in polycystin-1 (PC1), but the function of PC1 remains poorly understood. Here, we show that PC1 undergoes proteolytic cleavage that results in nuclear translocation of its cytoplasmic tail. The PC1 tail interacts with the transcription factor STAT6 and the coactivator P100, and it stimulates STAT6-dependent gene expression. Under normal conditions, STAT6 localizes to primary cilia of renal epithelial cells. Cessation of apical fluid flow results in nuclear translocation of STAT6. Cyst-lining cells in ADPKD exhibit elevated levels of nuclear STAT6, P100, and the PC1 tail. Exogenous expression of the human PC1 tail results in renal cyst formation in zebrafish embryos. These results identify a novel mechanism of cilia function in the transduction of a mechanical signal to changes of gene expression involving PC1 and show that this pathway is inappropriately activated in ADPKD.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping