Roles of the insulin-like growth factor I receptor C-terminus in cellular radioresistance.
Available evidence suggests that insulin-like growth factor I receptor (IGF-IR) expression leads to increased cellular radioresistance. The most direct explanation of these findings predicts that IGF-IR is the source of survival signals in resistant cells. Mutational analysis revealed that protein truncated at amino acid 1245 in the C-terminus retained the ability of IGF-IR to confer radioresistance whereas point mutations at both Tyr-1250 and Tyr-1251 abrogated this effect using IGF-IR-deficient mouse embryo fibroblasts (R-) as a recipient. In cells expressing the latter mutant receptors, both phosphatidylinositol-3(') kinase (PI3-K) and mitogen-activated protein kinase (MAPK) signaling pathways remained intact, and addition of exogenous IGF-I could not change the radiosensitivity of these cells. Further analysis indicated that the abrogation of radioresistance required the presence of His-1293 and Lys-1294. These results suggest a novel regulatory role of the C-terminus of IGF-IR in mediating cellular radioresistance that may be independent of survival signals transmitted through this receptor.
Molecular Diagnosis and Therapeutics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Dong
D
Yu
Hitoshi
H
Shibuya
Masahiko
M
Miura
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000737:chemistry / Q000502:physiology* / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000737:chemistry* / Q000502:physiology*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D017526:Receptor, IGF Type 1