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- Title
Sonic Hedgehog signaling impairs ionizing radiation--induced checkpoint activation and induces genomic instability.
- Authors
Leonard, Jennifer M.; Hang Ye; Wetmore, Cynthia; Karnitz, Larry M.
- 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[sup +/-] 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.
- Subjects
CELLULAR signal transduction; TUMORS; IONIZING radiation; CARCINOGENESIS; LABORATORY mice
- Publication
Journal of Cell Biology, 2008, Vol 183, Issue 3, p385
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.200804042