Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor.
Recently, p53 was demonstrated to affect the expression of the insulin-like growth factor 1 receptor (IGF-1R), a receptor tyrosine kinase that plays a crucial role in growth and survival of cancer cells. However, the underlying mechanisms for interaction between p53 and IGF-1R are still not fully understood. One of the ... challenging questions remaining to be answered is why the wild-type p53, which per se represses the transcription of the IGF-1R gene, in overexpressed form is necessary for a high IGF-1R expression. In this study, we show that inhibition of p53 causes ubiquitination and down-regulation, through increased degradation, of the IGF-1R in human malignant melanoma cells. This effect, which was independent of the p53 status (i.e., wild type or mutated), was prevented if Mdm2 was coinhibited. Similar results were obtained in UV-irradiated human melanocytes (harboring wild-type p53), in which level of the IGF-1R increased after up-regulation of p53. Interestingly, the basal ubiquitination of the IGF-1R in untreated cells also depended on Mdm2. We could prove that Mdm2 physically associates with IGF-1R and that Mdm2 causes IGF-1R ubiquitination in an in vitro assay. Taken together our data provide evidence that Mdm2 serves as a ligase in ubiquitination of the IGF-1R and thereby causes its degradation by the proteasome system. Consequently, by sequestering Mdm2 in the cell nuclei, the level of p53 may indirectly influence the expression of IGF-1R. This role of Mdm2 and p53 represents an unexpected mechanism for the regulation of IGF-1R and cell growth.
Mesh Terms:
3T3 Cells, Animals, Cell Nucleus, Down-Regulation, Genes, p53, Humans, Melanoma, Mice, Neoplasm Proteins, Nuclear Proteins, Oligodeoxyribonucleotides, Antisense, Peptide Hydrolases, Proteasome Endopeptidase Complex, Protein Interaction Mapping, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Receptor, IGF Type 1, Recombinant Fusion Proteins, Transfection, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Ubiquitin, Ultraviolet Rays
3T3 Cells, Animals, Cell Nucleus, Down-Regulation, Genes, p53, Humans, Melanoma, Mice, Neoplasm Proteins, Nuclear Proteins, Oligodeoxyribonucleotides, Antisense, Peptide Hydrolases, Proteasome Endopeptidase Complex, Protein Interaction Mapping, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Receptor, IGF Type 1, Recombinant Fusion Proteins, Transfection, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Ubiquitin, Ultraviolet Rays
Proc. Natl. Acad. Sci. U.S.A.
Date: Jul. 08, 2003
PubMed ID: 12821780
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