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'Achilles' heel' of key anti-cancer protein

Date:
February 13, 2017
Source:
Rockefeller University Press
Summary:
Researchers have discovered that a protein called Importin-11 protects the anti-cancer protein PTEN from destruction by transporting it into the cell nucleus. The research suggests that the loss of Importin-11 may destabilize PTEN, leading to the development of lung, prostate, and other cancers.
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Researchers at Cold Spring Harbor Laboratory in New York have discovered that a protein called Importin-11 protects the anti-cancer protein PTEN from destruction by transporting it into the cell nucleus. The study, "The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein," which will be published online February 13 in The Journal of Cell Biology, suggests that the loss of Importin-11 may destabilize PTEN, leading to the development of lung, prostate, and other cancers.

PTEN prevents tumor cells from growing uncontrollably, and mutations in the gene encoding this protein are commonly found in many different types of cancer. Some patients, however, show low levels of the PTEN protein even though their PTEN genes are normal. Lloyd Trotman, Muhan Chen, Dawid Nowak, and colleagues discovered that this may be due to defects in a protein called Importin-11 that transports PTEN into the nucleus, sheltering PTEN from cytoplasmic proteins that would otherwise target it for 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. Trotman and colleagues 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.

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 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 anti-cancer protein.

In prostate cancer, loss of Importin-11 predicted disease relapse and metastasis in patients who had had their prostates removed. "We think that the degradation of PTEN after loss or impairment of Importin-11 is a very effective driver of human prostate cancer," says Trotman. "Our results suggest that Importin-11 is the "Achilles' heel" of the ubiquitination system that maintains the correct levels of PTEN inside cells."


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Journal Reference:

  1. Muhan Chen, Dawid G. Nowak, Navneet Narula, Brian Robinson, Kaitlin Watrud, Alexandra Ambrico, Tali M. Herzka, Martha E. Zeeman, Matthias Minderer, Wu Zheng, Saya H. Ebbesen, Kendra S. Plafker, Carlos Stahlhut, Victoria M.Y. Wang, Lorna Wills, Abu Nasar, Mireia Castillo-Martin, Carlos Cordon-Cardo, John E. Wilkinson, Scott Powers, Raffaella Sordella, Nasser K. Altorki, Vivek Mittal, Brendon M. Stiles, Scott M. Plafker, Lloyd C. Trotman. The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. The Journal of Cell Biology, 2017; jcb.201604025 DOI: 10.1083/jcb.201604025

Cite This Page:

Rockefeller University Press. "'Achilles' heel' of key anti-cancer protein." ScienceDaily. ScienceDaily, 13 February 2017. <www.sciencedaily.com/releases/2017/02/170213131514.htm>.
Rockefeller University Press. (2017, February 13). 'Achilles' heel' of key anti-cancer protein. ScienceDaily. Retrieved March 30, 2017 from www.sciencedaily.com/releases/2017/02/170213131514.htm
Rockefeller University Press. "'Achilles' heel' of key anti-cancer protein." ScienceDaily. www.sciencedaily.com/releases/2017/02/170213131514.htm (accessed March 30, 2017).