Delayed activation of insulin-like growth factor-1 receptor/Src/MAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor.
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.
Criswell
Tracy
T
Department of Radiation Oncology and Program in Molecular and Cellular Basis of Disease, Laboratory of Molecular Stress Responses, Case Comprehensive Cancer Center, Cleveland, Ohio 44106-7285, USA.
Beman
Meghan
M
Araki
Shinako
S
Leskov
Konstantin
K
Cataldo
Eva
E
Mayo
Lindsey D
LD
Boothman
David A
DA
D045744:Cell Line, Tumor; D002470:Cell Survival; D051152:Clusterin; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
C495242:CLU protein, human; D051152:Clusterin; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D006023:Glycoproteins; D017874:Immediate-Early Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D014157:Transcription Factors; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases