Sonic Hedgehog signaling impairs ionizing radiation-induced checkpoint activation and induces genomic instability.
J Cell Biol
; 183(3): 385-91, 2008 Nov 03.
Article
em En
| MEDLINE
| ID: mdl-18955550
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Radiação Ionizante
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Receptores de Superfície Celular
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Instabilidade Genômica
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Proteínas Hedgehog
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Cell Biol
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos