PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2

Cell. 2002 Apr 19;109(2):157-68. doi: 10.1016/s0092-8674(02)00716-x.

Abstract

Autosomal dominant polycystic kidney disease is characterized by cyst formation in the kidney and other organs and results from mutations of PKD1 or PKD2. Previous studies suggest that their gene products have an important role in growth regulation. We now show that expression of polycystin-1 activates the JAK-STAT pathway, thereby upregulating p21(waf1) and inducing cell cycle arrest in G0/G1. This process requires polycystin-2, a channel protein, as an essential cofactor. Mutations that disrupt polycystin-1/2 binding prevent activation of the pathway. Mouse embryos lacking Pkd1 have defective STAT1 phosphorylation and p21(waf1) induction. These results suggest that one function of the polycystin-1/2 complex is to regulate the JAK/STAT pathway and explain how mutations of either gene can result in dysregulated growth.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Cycle / genetics*
  • Cell Division / genetics
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics*
  • DNA-Binding Proteins / genetics
  • Female
  • G1 Phase / genetics
  • Humans
  • Janus Kinase 2
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mutation / genetics
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Polycystic Kidney, Autosomal Dominant / metabolism
  • Protein-Tyrosine Kinases / genetics*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins*
  • Resting Phase, Cell Cycle / genetics
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction / genetics
  • TRPP Cation Channels
  • Trans-Activators / genetics

Substances

  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Membrane Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • TRPP Cation Channels
  • Trans-Activators
  • polycystic kidney disease 1 protein
  • polycystic kidney disease 2 protein
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Jak2 protein, mouse
  • Janus Kinase 2