Researchers from Northwestern University have stumbled upon a previously unobserved function of a protein found in the cell nuclei of all flora and fauna. In addition to exporting materials out of the nucleus, the protein, called Exportin-1 (also called Xpo1 or Crm1), seems to play a role in promoting gene transcription, the process that creates RNA replicas of strands of DNA to express genes.
Transcription factors, which regulate transcription, can also direct genes to interact with the nuclear pore complex, which serves as a conduit for molecules to move into or out of the nucleus. Exportin-1, the researchers found, forms a link between the two. By tethering transcription factors - and with them, hundreds of genes - to nuclear pore proteins, genes are moved to the edge of the nucleus, stimulating stronger gene expression.
"Because Exportin-1 is often overexpressed in cancers and leukemia, this work also raises the possibility that this newly discovered function is important in promoting cancer growth," said Molecular Biosciences Professor Jason Brickner, who led the study. "The work provides a molecular explanation for a phenomenon I discovered 20 years ago - the movement of genes to the nuclear periphery when they are turned on."
Brickner's 20 years of research in the department of molecular biosciences at Northwestern's Weinberg College of Arts & Sciences has mainly focused on yeast, an organism he says is "an excellent model for eukaryotic cells" because it has many features in its nucleus that are present universally across all plants, animals and fungi. Because Exportin-1 is found in all these organisms, the way it interacts with the genome may be true in all eukaryotes.
The interdisciplinary and cross-institutional team employed a variety of methods to untangle Exportin-1's specific functions in budding yeast, including single molecule tracking, chromatin localization in live cells, genome-wide mapping and biochemistry.
The unexpected findings, published today (March 20) in the journal Molecular Cell, could aid other scientists as they seek to develop new medications that stymie cancer growth without harming healthy cellular function.
"Exportin-1 is overexpressed in many leukemias and cancers. Because it binds to the genome, it may alter transcription to promote oncogenesis," said Northwestern Ph.D. student and first author Tiffany Ge. "Inhibitors of Exportin-1 are given to patients who fail to respond to first- or second-line chemotherapies. But these therapies are very toxic and have many side effects because they block all nuclear export, which is an essential function of cells."
A renewed understanding of the protein's dual role introduces the possibility that its overexpression promotes cancer development by enhancing the expression of genes responsible for cell division. Inhibiting just this process without impacting nuclear export could lead to the production of better medications. Whether Exportin-1's role in transcription is also essential and would give medications a similarly toxic effect, however, has not yet been tested.
Before drug development is considered, the researchers hope to confirm that the interaction between transcription factors and Exportin-1 is generalizable across species, as well as better define the specifics of the molecular interaction.
The research was supported by the National Institutes of Health (grants R35 GM136419, P41 GM109824, R01 GM112108, T32 NIGMS GM008061 and F32 GM153164) and a predoctoral fellowship from the National Science Foundation.
