TY - JOUR
T1 - Delayed activation of insulin-like growth factor-1 receptor/Src/ MAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor
AU - Criswell, Tracy
AU - Beman, Meghan
AU - Araki, Shinako
AU - Leskov, Konstantin
AU - Cataldo, Eva
AU - Mayo, Lindsey D.
AU - Boothman, David A.
PY - 2005/4/8
Y1 - 2005/4/8
N2 - Secretory clusterin protein (sCLU) is a general genotoxic stress-induced, pro-survival gene product implicated in aging, obesity, heart disease, and cancer. However, the regulatory signal transduction processes that control sCLU expression remain undefined. Here, we report that induction of sCLU is delayed, peaking 72 h after low doses of ionizing radiation, and is dependent on the up-regulation of insulin-like growth factor-1 as well as phosphorylation- dependent activation of its receptor (IGF-1 and IGF-1R, respectively). Activated IGF-1R then stimulates the downstream Src-Mek-Erk signal transduction cascade to ultimately transactivate the early growth response-1 (Egr-1) transcription factor, required for sCLU expression. Thus, ionizing radiation exposure causes stress-induced activation of IGF-1R-Src-Mek-Erk-Egr-1 signaling that regulates the sCLU pro-survival cascade pathway, important for radiation resistance in cancer therapy.
AB - Secretory clusterin protein (sCLU) is a general genotoxic stress-induced, pro-survival gene product implicated in aging, obesity, heart disease, and cancer. However, the regulatory signal transduction processes that control sCLU expression remain undefined. Here, we report that induction of sCLU is delayed, peaking 72 h after low doses of ionizing radiation, and is dependent on the up-regulation of insulin-like growth factor-1 as well as phosphorylation- dependent activation of its receptor (IGF-1 and IGF-1R, respectively). Activated IGF-1R then stimulates the downstream Src-Mek-Erk signal transduction cascade to ultimately transactivate the early growth response-1 (Egr-1) transcription factor, required for sCLU expression. Thus, ionizing radiation exposure causes stress-induced activation of IGF-1R-Src-Mek-Erk-Egr-1 signaling that regulates the sCLU pro-survival cascade pathway, important for radiation resistance in cancer therapy.
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U2 - 10.1074/jbc.M412569200
DO - 10.1074/jbc.M412569200
M3 - Article
C2 - 15689620
AN - SCOPUS:17144414465
SN - 0021-9258
VL - 280
SP - 14212
EP - 14221
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -