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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cerebellar Neoplasms / epidemiology
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Cerebellar Neoplasms / genetics
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Cerebellar Neoplasms / prevention & control
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Checkpoint Kinase 1
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Checkpoint Kinase 2
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DNA Damage / genetics
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DNA Damage / radiation effects
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DNA, Single-Stranded / genetics
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DNA, Single-Stranded / radiation effects
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Genomic Instability / genetics*
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Genomic Instability / physiology
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Hedgehog Proteins / physiology*
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Humans
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / physiology
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Medulloblastoma / epidemiology
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Medulloblastoma / genetics
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Medulloblastoma / prevention & control
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Mice
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Mice, Knockout
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Neoplasms / genetics
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Patched Receptors
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Patched-1 Receptor
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Protein Kinases / physiology
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Protein Serine-Threonine Kinases / physiology
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Radiation, Ionizing*
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics*
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Zinc Finger Protein GLI1
Substances
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DNA, Single-Stranded
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Gli1 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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PTCH1 protein, human
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Patched Receptors
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Patched-1 Receptor
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Ptch1 protein, mouse
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Receptors, Cell Surface
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Zinc Finger Protein GLI1
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Protein Kinases
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Checkpoint Kinase 2
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CHEK1 protein, human
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CHEK2 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases