Chen, M., Nowak, D. G., Narula, N., Robinson, B., Watrud, K., Ambrico, A., Herzka, T. M., Zeeman, M. E., Minderer, M., Zheng, W., Ebbesen, S. H., Plafker, K. S., Stahlhut, C., Wang, V. M., Wills, L., Nasar, A., Castillo-Martin, M., Cordon-Cardo, C., Wilkinson, J. E., Powers, S., Sordella, R., Altorki, N. K., Mittal, V., Stiles, B. M., Plafker, S. M., Trotman, L. C. (March 2017) The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. J Cell Biol, 216 (3). pp. 641-656. ISSN 0021-9525
Abstract
Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, are limiting factors for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.
| Item Type: | Paper |
|---|---|
| Subjects: | 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 > genes: types > tumor suppressor |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Signal Transduction CSHL labs > Powers lab CSHL labs > Sordella lab CSHL labs > Trotman lab School of Biological Sciences > Publications CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | 6 March 2017 |
| Date Deposited: | 16 Feb 2017 20:58 |
| Last Modified: | 26 Oct 2020 16:44 |
| PMCID: | PMC5350510 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/34123 |
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