Two Key Players in Cancer Prevention and How They Work

• Cancer • Dec 15, 05

Mayo Clinic researchers have challenged the conventional teaching about a common cancer trait and in doing so, discovered how cells are naturally “cancer proofed.” Their findings appear in today’s early online edition of the Dec. 15 issue of the journal Nature (http://www.nature.com/nature ).

The researchers investigated aneuploidy (AN-u-ploy-dee), the state in which a cell has an abnormal number of chromosomes that creates cellular instability, giving rise to tumors. They discovered two key proteins that help prevent aneuploidy, and also found how the proteins work to “cancer proof” a cell: by preventing premature segregation of duplicated chromosomes during (nuclear) cell division.

Significance of the Mayo Clinic Research
These new cancer players comprise a two-protein complex Rae1-Nup98. This complex works together to stabilize healthy cells by functioning as a kind of cell-division auditing system that makes sure the right number of chromosomes is distributed in each part of a newly divided cell. By so doing, they promote “euploidy”—the ideal chromosomal distribution needed for stability, and the opposite of aneuploidy.

“What we discovered is that there’s an active process of cellular machinery that prevents aneuploidy,” says Mayo cancer researcher Jan van Deursen, Ph.D., who led the research team. “It’s a surveillance mechanism involving the two proteins Rae1-Nup98 that makes sure that in every cell division the proper number of chromosomes occur.”

Dr. van Deursen says the findings help set the stage for the development of a new generation of cancer treatments that are more effective and gentler than the current radiation and chemotherapy treatments used. “The reason we are investigating this in the first place is because 95 percent of all human cancers involve aneuploidy,” he says. “When researchers show—as we have just done—new mechanisms that prevent aneuploidy, we are helping improve the understanding of the basic science that we hope will lead to new cancer treatments one day.”

Background Biology

A mutation in a cell’s DNA can lead to tumor development by turning off the body’s natural tumor suppression genes, or by turning on oncogenes—special genes that promote cancer. For example, in at least 15 forms of human leukemia, Nup98 is found to be mutated.
Aneuploidy plays a role in most cancers by making them unstable so they grow out of control. For years in labs around the world experiments using aneuploidic mice versus normal mice showed that if both groups are exposed to carcinogens, both groups develop tumors. But the aneuploidic mice get significantly more tumors. That prompted the urgent question the Mayo Clinic investigators set out to answer: How does aneuploidy arise?
Until now, standard teaching held that aneuploidy’s mechanism of action was controlled by a single cellular system. The Mayo discovery challenges and revises this by proving a second aneuploidy regulatory system is at work: the Rae1-Nup98 complex.

How Mayo Discovered the Importance of Rae1-Nup98
Errors in one step of cell growth can undermine the entire process. The Mayo researchers saw this happen when they used specially bred mice and lowered the amounts of the two proteins Rae1-Nup98—which were not previously known to be involved in aneuploidy regulation. The results: Insufficient Rae1-Nup98 threw off the timing of the cell growth process that correctly distributes chromosomes. Low Rae1-Nup98 caused three crucial missteps:

1) premature separation of cell components known as sister chromatids
2) severe aneuploidy, resulting in instability
3) mistimed degradation of a kind of glue that keeps the sister chromatids together. If that glue lets go at the wrong time, the sister chromatids separate in the wrong way. Then they aren’t properly lined up for the next step in the choreography of healthy cell division. The result of being in the wrong place at the wrong time is that they can’t connect with the next partner; a healthy cell process is undermined; chromosomes are not correctly distributed; aneuploidy—the precondition for cancers—arises. The cell is now unstable and therefore especially vulnerable to mutation.

Collaboration and Support
The Mayo research team also included co-authors Karthik Jeganathan and Liviu Malureanu, M.D. Their work was supported by grants from the National Institutes of Health.