Sonic Hedgehog signaling impairs ionizing radiation-induced checkpoint activation and induces genomic instability

J Cell Biol. 2008 Nov 3;183(3):385-91. doi: 10.1083/jcb.200804042. Epub 2008 Oct 27.

Abstract

The Sonic Hedgehog (Shh) pathway plays important roles in embryogenesis, stem cell maintenance, tissue repair, and tumorigenesis. Haploinsufficiency of Patched-1, a gene that encodes a repressor of the Shh pathway, dysregulates the Shh pathway and increases genomic instability and the development of spontaneous and ionizing radiation (IR)-induced tumors by an unknown mechanism. Here we show that Ptc1(+/-) mice have a defect in the IR-induced activation of the ATR-Chk1 checkpoint signaling pathway. Likewise, transient expression of Gli1, a downstream target of Shh signaling, disrupts Chk1 activation in human cells by preventing the interaction of Chk1 with Claspin, a Chk1 adaptor protein that is required for Chk1 activation. These results suggest that inappropriate Shh pathway activation promotes tumorigenesis by disabling a key signaling pathway that helps maintain genomic stability and inhibits tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellar Neoplasms / epidemiology
  • Cerebellar Neoplasms / genetics
  • Cerebellar Neoplasms / prevention & control
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • DNA Damage / genetics
  • DNA Damage / radiation effects
  • DNA, Single-Stranded / genetics
  • DNA, Single-Stranded / radiation effects
  • Genomic Instability / genetics*
  • Genomic Instability / physiology
  • Hedgehog Proteins / physiology*
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / physiology
  • Medulloblastoma / epidemiology
  • Medulloblastoma / genetics
  • Medulloblastoma / prevention & control
  • Mice
  • Mice, Knockout
  • Neoplasms / genetics
  • Patched Receptors
  • Patched-1 Receptor
  • Protein Kinases / physiology
  • Protein Serine-Threonine Kinases / physiology
  • Radiation, Ionizing*
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics*
  • Zinc Finger Protein GLI1

Substances

  • DNA, Single-Stranded
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • PTCH1 protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Receptors, Cell Surface
  • Zinc Finger Protein GLI1
  • Protein Kinases
  • Checkpoint Kinase 2
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Chek2 protein, mouse
  • Protein Serine-Threonine Kinases