Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. Academic Article uri icon

Overview

MeSH

  • 3T3 Cells
  • Animals
  • Blotting, Western
  • DNA Primers
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Genomics
  • Histone Deacetylases
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Mice
  • Microscopy, Electron, Transmission
  • Nerve Tissue Proteins
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Zebrafish

MeSH Major

  • Cilia
  • Hedgehog Proteins
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Wnt Proteins

abstract

  • The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies.

publication date

  • January 25, 2011

has subject area

  • 3T3 Cells
  • Animals
  • Blotting, Western
  • Cilia
  • DNA Primers
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Genomics
  • Hedgehog Proteins
  • Histone Deacetylases
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Mice
  • Microscopy, Electron, Transmission
  • Nerve Tissue Proteins
  • Protein-Serine-Threonine Kinases
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Wnt Proteins
  • Zebrafish

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3790583

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2001225

PubMed ID

  • 21266715

Additional Document Info

start page

  • ra4

volume

  • 4

number

  • 157