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

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.

SUBMITTER: Leonard JM

PROVIDER: S-EPMC2575780 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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

Leonard Jennifer M JM Ye Hong H Wetmore Cynthia C Karnitz Larry M LM

The Journal of cell biology 20081027 3

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 pathwa ...[more]

PMID: 18955550

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