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Nuclear Pore Complexes Offer Clues to Gene Expression and Cancer

Matt Weitzman

Polytene chromosomes revealed that nucleoporins pull double duty as transcription factors regulating the activity of genes active during early development.

Not only do nuclear pore complexes serve as communication channels between molecules and a cell's nucleus, but researchers at the Salk Institute have now shown that some of the pores' constituent proteins, called nucleoporins, also pull double duty to regulate gene activity.

This marks the first time nucleoporins' gene regulatory function has been demonstrated in multicellular organisms. These findings not only reveal a new class of transcription factors but they may offer new insights into the mechanisms behind cancer.

It was previously unknown whether similar regulatory properties were present in multicellular organisms. For more than a decade, however, scientists had known that when the protein called Nup98, a nucleoporin, abnormally fuses with certain proteins that regulate gene expression, causing leukemia. What is more, nucleoporins Nup214 and Nup88 are highly over-expressed in other cancers, including colon cancer and very aggressive forms of lung cancer.

Scientists had long questioned why these components of the cell's transport channel are implicated in cancer and had theorized that the connection might stem from a problem related to the conveyance of molecules in and out of the nucleus.

To probe the role of these proteins, Martin Hetzer, Hearst Endowment associate professor in Salk's Molecular and Cell Biology Laboratory, and his group studied the development of salivary glands in fruit flies. Using antibodies, the scientists were able to detect the binding of Nup98, SEC13, and FG-containing nucleoporins to specific genes on the polytene chromosomes. When they did a three-dimensional reconstruction of the nuclei, they found the nucleoporins inside the nucleus.

"Very few studies have looked at nuclear pore components for their potential role in gene regulation in animal cells," says Hetzer. "The fact that NPC components can interact with genes inside the nucleus makes a lot more sense in how they can regulate gene activity. The gene doesn't go to the pore; the pore protein goes to the gene."

The nucleoporins don't regulate all genes, but are required for a subset of genes, including developmentally regulated genes, which are turned on and off in a controlled manner during cell differentiation and tissue development.

"What is exciting to us is that they are key regulators for developmental genes and also potential markers for causes of cancer," Hetzer explains.