Negative regulation of p53 by the long isoform of ErbB3 binding protein Ebp1 in brain tumors.
The ErbB3 binding protein Ebp1 has been implicated in a number of human cancers. Ebp1 includes 2 isoforms, p48 and p42, that exhibit different cellular activities. Here we show that the larger p48 isoform is transforming and that it promotes cell growth, clonogenicity, and invasion in human glioblastoma (GBM). P48 ... overexpression in GBM cells facilitated tumorigenesis and enhanced tumor growth in mouse xenograft models. Human GBM tissues displayed elevated levels of p48 compared with surrounding normal tissues or low-grade tumors. Notably, p48 levels were inversely correlated with poor prognosis in GBM patients. We determined that p48 binds to the p53 E3 ligase HDM2, enhancing HDM2-p53 association and thereby promoting p53 polyubiquitination and degradation to reduce steady-state p53 levels and activity. Together, our findings suggest that p48 functions as an oncogene by promoting glioma tumorigenicity via interactions with HDM2 that contribute to p53 downregulation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Cell Survival, Gene Expression Regulation, Neoplastic, Glioblastoma, HCT116 Cells, Humans, Immunoblotting, Mice, Mice, Nude, NIH 3T3 Cells, Neoplasm Invasiveness, Neoplasms, Experimental, Proteasome Endopeptidase Complex, Protein Binding, Protein Isoforms, Proto-Oncogene Proteins c-mdm2, RNA Interference, RNA-Binding Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Tumor Suppressor Protein p53, Ubiquitination
Adaptor Proteins, Signal Transducing, Animals, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Cell Survival, Gene Expression Regulation, Neoplastic, Glioblastoma, HCT116 Cells, Humans, Immunoblotting, Mice, Mice, Nude, NIH 3T3 Cells, Neoplasm Invasiveness, Neoplasms, Experimental, Proteasome Endopeptidase Complex, Protein Binding, Protein Isoforms, Proto-Oncogene Proteins c-mdm2, RNA Interference, RNA-Binding Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Tumor Suppressor Protein p53, Ubiquitination
Cancer Res.
Date: Dec. 01, 2010
PubMed ID: 21098709
View in: Pubmed Google Scholar
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- Interactions 4
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