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September 19, 2018

Nuclear Pore Control May Stop Cancer Cells from Proliferating

Salk scientists develop method to manipulate numbers of nuclear pores. [Salk Institute]

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    Cells with the Tpr protein (top row) have fewer nuclear pores than cells without the protein (bottom row). The right column shows a close-up of the pore density, with many more pores appearing in the absence of Tpr (bottom left). [Salk Institute]

    Scientists at the Salk Institute report (“Tpr regulates the total number of nuclear pore complexes per cell nucleus”) in Genes & Development that they have devised a way to manipulate numbers of individual nuclear pores that may one day stop cancerous cells from proliferating out of control.

    "Previously, we didn't have the tools to artificially increase nuclear pores," says lead author Martin Hetzer, Ph.D., who is also Salk's vice president and CSO. "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?"

    Nuclear pores are essential elements of all cells that provide controlled ways to move cellular material in and out of a nucleus. In organisms ranging from fungi to mammals, individual cells possess these transport channels that mediate a thousand events per second. Individual nuclear pores are fashioned from multiple copies of 30 proteins known as nucleoporins. Dr. Hetzer and colleagues looked at the nucleoporin Tpr, which has been implicated in certain cancers. 

    “The total number of nuclear pore complexes (NPCs) per nucleus varies greatly between different cell types and is known to change during cell differentiation and cell transformation. However, the underlying mechanisms that control how many nuclear transport channels are assembled into a given nuclear envelope remain unclear. Here, we report that depletion of the NPC basket protein Tpr, but not [nucleoporin; Nup] Nup153, dramatically increases the total NPC number in various cell types. This negative regulation of Tpr occurs via a phosphorylation cascade of extracellular signal-regulated kinase (ERK), the central kinase of the mitogen-activated protein kinase (MAPK) pathway,” write the investigators.

    “Tpr serves as a scaffold for ERK to phosphorylate Nup153, which is critical for early stages of NPC biogenesis. Our results reveal a critical role of the Nup Tpr in coordinating signal transduction pathways during cell proliferation and the dynamic organization of the nucleus.”

    The team showed, for the first time, that each of the transport channels within a cell is unique, and each cell nucleus possesses a specific number of nuclear pores. Next, the team used molecular methods to remove Tpr to see its effect on the number of nuclear pores, with a surprising result.

    "Typically, when you knockdown or remove some of the proteins that make up the nuclear pore complex, the total number of nuclear pores goes down," says Asako McCloskey, Ph.D., first author of the paper and a Salk research associate. "Our surprising finding was that when we get rid of the nucleoporin Tpr, nuclear pore numbers went up dramatically."

    "This is the first time that modifying a component within the transport channel has been shown to increase the number of nuclear pores," adds Dr. Hetzer.

    This indicates that Tpr plays a role not in transport itself, but in regulating the assembly of nuclear pores. The knowledge could be crucial for future attempts to manipulate numbers of nuclear pores to treat disease. 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 cancer-related "cargo" proteins from being transported through the nuclear pores can lead to dramatic effects in cancer treatment. Targeting nuclear pores could also negate aggressive cancer's resistance to multiple drugs, as higher numbers of nuclear pores in tumor cells allow for more export of chemotherapy out of the nuclei. 

    Next, the lab will use the new technique to pinpoint the effects of tweaking nuclear pore numbers in a variety of cell types.

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