TY - JOUR
T1 - Sonic Hedgehog signaling impairs ionizing radiation - Induced checkpoint activation and induces genomic instability
AU - Leonard, Jennifer M.
AU - Ye, Hong
AU - Wetmore, Cynthia
AU - Karnitz, Larry M.
PY - 2008/11/3
Y1 - 2008/11/3
N2 - The Sonic Hedgehog (Shh) pathway plays important roles in embryogenesis, stem cell maintenance, tissue repair, and tumorigenesis. Haploinsuffi ciency 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.
AB - The Sonic Hedgehog (Shh) pathway plays important roles in embryogenesis, stem cell maintenance, tissue repair, and tumorigenesis. Haploinsuffi ciency 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.
UR - http://www.scopus.com/inward/record.url?scp=56149098985&partnerID=8YFLogxK
U2 - 10.1083/jcb.200804042
DO - 10.1083/jcb.200804042
M3 - Article
C2 - 18955550
AN - SCOPUS:56149098985
SN - 0021-9525
VL - 183
SP - 385
EP - 391
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 3
ER -