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The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein
- Source :
- The Journal of Cell Biology
- Publication Year :
- 2017
- Publisher :
- Rockefeller University Press, 2017.
-
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.<br />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.
- 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
Subjects
Details
- ISSN :
- 15408140 and 00219525
- Volume :
- 216
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Biology
- Accession number :
- edsair.doi.dedup.....31477751c8156743578470802ad370b5