Study: Salk scientists develop a method to manipulate the number of nuclear pores – (Details)

Salk Institute researchers reported on September 18, 2018 in the journal Genes & Development that they have devised a way to manipulate the number of individual nuclear pores – a breakthrough that could one day prevent cancer cells from proliferating out of control.

"Previously, we did not have the tools to artificially increase nuclear pores," says lead author Martin Hetzer, who is also vice president and scientific director of Salk. "Our study provides an experimental trail to ask critical questions: what are the consequences of increasing the number of nuclear pores in a healthy cell to mimic those found in a cancer cell? Does this affect the activity of genes? Why do cancer cells increase the number of nuclear pores?

Nuclear pores are essential elements of all cells that provide controlled means for moving cellular material in and out of the nucleus. In organisms ranging from fungi to mammals, individual cells have these transport channels that carry a thousand events per second. Individual nuclear pores are made from multiple copies of proteins called nucleoporins. Hetzer and his colleagues examined the nucleoporin Tpr, implicated in some cancers.

The team has shown, for the first time, that each of the transport channels in a cell is unique and that each cell nucleus has a specific number of nuclear pores. Then, the team used molecular methods to eliminate the Tpr to see its effect on the number of nuclear pores, with a surprising result.

"Generally, when you" knock down "or remove some of the proteins that make up the nuclear pore complex, the total number of nuclear pores decreases," says Asako McCloskey, lead author of the paper and research associate at Salk. "Our surprising discovery was that when we get rid of the nucleoporin Tpr, the number of nuclear pore has increased dramatically."

"It's the first time that changing a component in the transport channel increases the number of nuclear pores," adds Hetzer.

This indicates that Tpr plays a role not in the transport itself, but in regulating the assembly of nuclear pores. Knowledge could be crucial for future attempts to manipulate the number of nuclear pores to treat diseases. For example, cells with higher metabolic activity, such as stimulated thyroid follicular cells or aggressive tumors, have more nuclear pores per nucleus. Other research has shown that stopping the transport of cancer-related "cargo" proteins through nuclear pores can have dramatic effects on cancer treatment. Targeting nuclear pores could also negate the resistance of aggressive cancer to multiple drugs, as a higher number of nuclear pores in tumor cells allow them to export chemotherapy out of the nuclei.

Then, the lab will use the new technique to identify the effects of changing nuclear pore numbers in various cell types.

The other author of the diary is Arkaitz Ibarra, a molecular stethoscope scientist from San Diego.

The work was funded by the National Institutes of Health, the Helmsley Center for Genomic Medicine, the Nomis Foundation and the Glenn Center for Research on Aging.