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Epitomics: The Rabbit Monoclonal Company
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Published online September 10, 2007
doi:10.1083/jcb.200703044
The Journal of Cell Biology, Vol. 178, No. 6, 995-1007
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Xiong et al.
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Article

 A novel role for IGF-1R in p53-mediated apoptosis through translational modulation of the p53-Mdm2 feedback loop

Lei Xiong1, Fei Kou1, Ying Yang1, and Jiarui Wu1,2,3

1 Key Laboratory of Systems Biology and 2 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
3 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Science, University of Science and Technology of China, Hefei, Anhui 230026, China

Correspondence to J.Wu: wujr{at}sibs.ac.cn

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.

L. Xiong and F. Kou contributed equally to this paper.

Abbreviations used in this paper: BP1, binding protein 1; CHX, cycloheximide; CMV, cytomegalovirus; CrPV, cricket paralysis virus; eIF, eukaryotic translation initiation factor; ERK, extracellular signal-regulated kinase; GFP-p53DD, dominant-negative p53; GSK, glycogen synthase kinase; IGF-1R, insulin-like growth factor 1 receptor; IGF-1R-WT, wild-type IGF-1R; IGF-1R-YF, kinase-inactive IGF-1R; IRES, internal ribosome entry site; m7GTP, 7-methyl GTP; MEF, mouse embryonic fibroblast; mTOR, molecular target of rapamycin; PABP, poly(A)-binding protein; PARP, poly (ADP-ribose) polymerase; PI-3K, phosphoinositide-3 kinase; UTR, untranslated region.


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