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Published online
doi:10.1083/jcb.200804042
The Journal of Cell Biology, Vol. 183, No. 3, 385-391
The Rockefeller University Press, 0021-9525 $30.00
© Leonard et al.
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Sonic Hedgehog signaling impairs ionizing radiation–induced checkpoint activation and induces genomic instability



Jennifer M. Leonard1, Hong Ye2, Cynthia Wetmore1,2, and Larry M. Karnitz3,4,5

1 Department of Biochemistry and Molecular Biology, 2 Department of Pediatrics and Adolescent Medicine, 3 Department of Molecular Pharmacology and Experimental Therapeutics, 4 Department of Radiation Oncology, and 5 Division of Oncology Research, College of Medicine, Mayo Clinic, Rochester, MN 55905

Correspondence to Larry M. Karnitz: karnitz.larry{at}mayo.edu; or Cynthia Wetmore: wetmore.cynthia{at}mayo.edu

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.

Abbreviations used in this paper: BCNS, basal cell nevus syndrome; DSB, double strand break; HEK, human embryonic kidney; IR, ionizing radiation; MEF, mouse embryonic fibroblast; P, postnatal day; PTCH1, Patched-1; RPA, replication protein A; Shh, Sonic Hedgehog; SMOH, Smoothened; ssDNA, single stranded DNA.

© 2008 Leonard et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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