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To Fight Cancer, Manipulate Nuclear Pore Production

Nuclear pore concentrations in cells with Tpr (left) versus without (right). Credit: Salk Institute

Researchers have identified a type of protein that regulates the production of nuclear pores. Since an overabundance of nuclear pores has been associated with the aggressive formation of tumors, this discovery could have important implications for cancer treatment.

Nuclear pore complexes (NPCs), transport channels crucial to cell function, serve as portals to the cell nucleus and control the transport of proteins and RNA across the nuclear envelope. The number of NPCs in a cell is known to change during cell differentiation and transformation. How exactly that quantity is controlled has, until now, remained a mystery.

NPC assembly is a multi-stage process involving various nucleoporins (Nups), a protein family consisting of around 30 NPC building blocks. Since NPCs are highly stable structures once they have been assembled into the nuclear envelope, the researchers—Asako McCloskey, PhD, Arkaitz Ibarra, PhD, and Martin W. Hetzer, PhD, of The Salk Institute for Biological Studies—hypothesized that any mechanism controlling the number of NPCs would occur early in the course of NPC formation.

The researchers experimented with depleting Nup Elys, which binds chromatin; the transmembrane protein Pom121; the Nup107/160 complex; and the nuclear basket component Nup153, required for anchoring NPCs within the nuclear envelope. Depleting any of these nucleoporins prevented the creation of new NPCs, dramatically reducing their overall numbers. As the researchers state in their paper published in Genes & Development, these outcomes "confirm previous studies and support the notion that multiple Nups are required to coordinate the recruitment of [around] 30 different polypeptides to a new [nuclear envelope] assembly site."

They were surprised, however, when they investigated whether depleting nuclear basket component Tpr would affect NPC assembly. Tpr, the last nucleoporin added to NPCs in cell cycle phase G1, is known to play a role in certain cancers. The researchers found that reducing Tpr did not decrease NPC production. Instead, diminishing Tpr dramatically increased the total NPC count from an average of 3,000 NPCs per nucleus to an average nearing 5,000 per nucleus, with some nuclei even approaching 8,000 NPCs.

According to Dr. McCloskey, these findings are highly unusual: "Typically, when you… remove some of the proteins that make up the nuclear pore complex, the total number of nuclear pores goes down."

"This is the first time that modifying a component within the transport channel has been shown to increase the number of nuclear pores," concurred Dr. Hetzer, vice president and chief science officer at The Salk Institute and senior author of the study. "Previously, we didn't have the tools to artificially increase nuclear pores. Our study provides an experimental avenue to ask critical questions: What are the consequences of boosting the number of nuclear pores in a healthy cell to mimic those found in a cancer cell? Does this affect gene activity? Why do cancer cells increase the number of nuclear pores?"

The answers to these questions and the knowledge that Tpr plays a role in controlling NPC assembly could be vital to future attempts at manipulating NPC numbers for the treatment of aggressive tumors associated with an excess of nuclear pores.

For More Information

McCloskey A, Ibarra A, & Hetzer MW (2018). Tpr regulates the total number of nuclear pore complexes per cell nucleus. Genes & Development, 32:1-11. DOI:10.1101/gad.315523.118

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