Vulnerable Anticancer Protein Seeks Nuclear Sanctuary

Even when it is mutation-free and transcribed faithfully, the PTEN gene may fail to keep the cell adequately supplied with the PTEN, or phosphatase and tensin homolog, protein, a tumor-suppressor. Plainly, the PTEN gene is not at fault. The blame belongs to cytoplasmic proteins that target the PTEN protein for destruction. Actually, that’s not entirely fair. Some blame, it turns out, might also go to a nuclear gatekeeper called Importin-11. This nuclear transport receptor may be capable, or not, of welcoming the PTEN protein to the relatively safe confines of the nucleus.

The role of Importin-11 in protecting the PTEN protein emerged from a study conducted by researchers at Cold Spring Harbor Laboratory (CSHL). After taking up the question of why some patients show low levels of the PTEN protein, even though their PTEN genes are normal, the researchers discovered that the PTEN protein shortages may be due to defects in importin-11.

Details of this work appeared February 13 in the Journal of Cell Biology (JCB), in an article entitled, “The Nuclear Transport Receptor Importin-11 Is a Tumor Suppressor That Maintains PTEN Protein.” The article suggests that loss of Importin-11 may destabilize PTEN, leading to the development of lung, prostate, and other cancers.

“[We] find,” the article’s authors wrote, “that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, are limiting factors for PTEN degradation.”

Several cytoplasmic proteins—NEDD4-1, NDFIP1, and UBE2E1—combine to tag PTEN with the small molecule ubiquitin. PTEN tagged with multiple ubiquitin molecules can then be recognized and destroyed by the cell’s protein degradation machinery.

“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,” the article’s authors continued. “These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors.”

The CSHL researchers, led by Lloyd Trotman, Ph.D., found that Importin-11 protects PTEN from degradation by escorting not only PTEN but also UBE2E1 into the nucleus, thereby breaking up the cytoplasmic ubiquitination apparatus.

PTEN prevents tumor cells from growing uncontrollably, and mutations in the gene encoding this protein are commonly found in many different types of cancer. In the current study, mice lacking Importin-11 showed lower levels of PTEN protein and developed lung adenocarcinomas and prostate neoplasias.

Mutations in the gene encoding Importin-11 have been identified in human cancers, and Dr. Trotman and colleagues found that tumors from lung cancer patients lacking Importin-11 tended to show low PTEN levels as well. The researchers estimate that loss of Importin-11 may account for the loss of PTEN in approximately one-third of lung cancer patients lacking this key anticancer protein.

In prostate cancer, loss of Importin-11 predicted disease relapse and metastasis in patients who had had their prostates removed.

“[We] find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy,” noted the authors of the JCB article.

“We think that the degradation of PTEN after loss or impairment of Importin-11 is a very effective driver of human prostate cancer,” explained Dr. Trotman. “Our results suggest that Importin-11 is the ‘Achilles heel’ of the ubiquitination system that maintains the correct levels of PTEN inside cells.”