1. The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein
- Author
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Lorna Wills, Saya H. Ebbesen, Wu Zheng, Navneet Narula, Scott Powers, Kendra S. Plafker, Lloyd C. Trotman, Tali Herzka, Brian D. Robinson, Kaitlin Watrud, Vivek Mittal, Brendon M. Stiles, Nasser K. Altorki, Carlos Stahlhut, Dawid G. Nowak, John E. Wilkinson, Abu Nasar, Raffaella Sordella, Matthias Minderer, Carlos Cordon-Cardo, Mireia Castillo-Martin, Martha E. Zeeman, Alexandra Ambrico, Muhan Chen, Victoria M.-Y. Wang, and Scott M. Plafker
- Subjects
0301 basic medicine ,Cytoplasm ,Lung Neoplasms ,Phosphatase ,Receptors, Cytoplasmic and Nuclear ,Importin ,Biology ,Article ,Cell Line ,law.invention ,Metastasis ,Mice ,03 medical and health sciences ,law ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Tensin ,PTEN ,Receptor ,Research Articles ,Cell Nucleus ,Tumor Suppressor Proteins ,PTEN Phosphohydrolase ,Cell Biology ,beta Karyopherins ,medicine.disease ,3. Good health ,030104 developmental biology ,Ubiquitin-Conjugating Enzymes ,Cancer research ,biology.protein ,Suppressor ,Adenocarcinoma ,HeLa Cells - Abstract
Reduced PTEN protein is linked to tumorigenesis. Here, Chen et al. show that the nuclear transport receptor Importin-11 separates PTEN from degradation machinery. IPO11 mutant mice exhibit PTEN degradation, lung adenocarcinoma, and prostate neoplasia. In human prostatectomy patients, IPO11 status predicts disease recurrence and metastasis., 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, is a limiting factor 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.
- Published
- 2017