Wang, X., Trotman, L. C., Koppie, T., Alimonti, A., Chen, Z., Gao, Z., Wang, J., Erdjument-Bromage, H., Tempst, P., Cordon-Cardo, C., Pandolfi, P. P., Jiang, X. (January 2007) NEDD4-1 Is a Proto-Oncogenic Ubiquitin Ligase for PTEN. Cell, 128 (1). pp. 129-139. ISSN 00928674 (ISSN)
Abstract
The tumor suppressor PTEN, a critical regulator for multiple cellular processes, is mutated or deleted frequently in various human cancers. Subtle reductions in PTEN expression levels have profound impacts on carcinogenesis. Here we show that PTEN level is regulated by ubiquitin-mediated proteasomal degradation, and purified its ubiquitin ligase as HECT-domain protein NEDD4-1. In cells NEDD4-1 negatively regulates PTEN stability by catalyzing PTEN polyubiquitination. Consistent with the tumor-suppressive role of PTEN, overexpression of NEDD4-1 potentiated cellular transformation. Strikingly, in a mouse cancer model and multiple human cancer samples where the genetic background of PTEN was normal but its protein levels were low, NEDD4-1 was highly expressed, suggesting that aberrant upregulation of NEDD4-1 can posttranslationally suppress PTEN in cancers. Elimination of NEDD4-1 expression inhibited xenotransplanted tumor growth in a PTEN-dependent manner. Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53. © 2007 Elsevier Inc. All rights reserved.
| Item Type: | Paper |
|---|---|
| Additional Information: | PubMed ID: 17218260 |
| Uncontrolled Keywords: | mutant protein phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase proteasome protein MDM2 protein NEDD4 1 protein p53 tumor suppressor protein ubiquitin ubiquitin protein ligase ubiquitin protein ligase NEDD4 unclassified drug animal tissue article cancer cancer genetics cancer research carcinogenesis catalysis cell function cell transformation controlled study enzyme purification functional genomics functional proteomics gene function genetic analysis human human cell male mouse nonhuman priority journal protein analysis protein DNA interaction protein domain protein expression protein function protein processing proto oncogene tumor growth tumor suppressor gene ubiquitination upregulation xenotransplantation Animals Cell Transformation, Neoplastic Hela Cells Humans Mice Neoplasm Transplantation Neoplasms Polyubiquitin Protein Processing Post-Translational Protein Structure Tertiary Proto-Oncogenes PTEN Phosphohydrolase RNA Interference Substrate Specificity Ubiquitin-Protein Ligases |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation |
| CSHL Authors: | |
| Communities: | CSHL labs > Trotman lab |
| Depositing User: | Brian Soldo |
| Date: | January 2007 |
| Date Deposited: | 23 Mar 2012 16:08 |
| Last Modified: | 08 May 2013 16:38 |
| PMCID: | PMC1828909 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/25530 |
Actions (login required)
 |
Administrator's edit/view item |
