A novel role for IGF-1R in p53-mediated apoptosis through translational modulation of the p53-Mdm2 feedback loop.
Insulin-like growth factor 1 receptor (IGF-1R) is important in cancer cell growth and survival and has been implicated in cancer pathophysiology and treatment. Here we report a novel function for IGF-1R in p53-dependent apoptotic response. We show that inhibition or loss of IGF-1R activity reduces translational synthesis of p53 and Mdm2 protein. Notably, IGF-1R inhibition increases p53 protein stability by reducing p53 ubiquitination and maintains p53 at low levels by decreasing p53 synthesis, thus rendering p53 insensitive to stabilization after DNA damage. The accumulation and apoptosis of DNA-damage-induced p53 is therefore reduced in Igf-1r(-/-) mouse embryonic fibroblasts or tumor cells treated with the IGF-1R inhibitor. Furthermore, we find that inhibition of IGF-1R reduces p53 and Mdm2 translation through a gene-specific mechanism mediated by the respective 5' untranslated region of p53 and mdm2 messenger RNA. The eukaryotic translation initiation factor 4F complex is also involved in this translational inhibition. These results demonstrate an unexpected role for translational control by IGF-1R in p53-mediated apoptosis.
Xiong
Lei
L
Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Kou
Fei
F
Yang
Ying
Y
Wu
Jiarui
J
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002478:Cells, Cultured; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
D020121:5' Untranslated Regions; D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D017526:Receptor, IGF Type 1