Defining an elaborate yet fragile control pathway offers a new strategy for toppling many cancers.

Cancer cells are tough, insidious survivors. They deftly use their aberrant genes to subvert normal cellular controls and trigger explosive, often lethal, growth. Given this impressive proficiency, researchers don't expect to discover weaknesses in cancer cells' malignant strategy.

However, HHMI investigator Michael R. Green and his colleagues at the University of Massachusetts Medical School have uncovered just such a weakness—one they hope is fatal for cancer cells. They have found that a major cancer-promoting gene, ras, relies on a complex, and gratifyingly vulnerable, “house-of-cards” control pathway to enable tumor cell survival.

This pathway is so precarious that removing just one component could bring cancer cells collapsing down to their death, the scientists have learned. The elaborate pathway depends on more than half a deck of molecular cards—the proteins produced by 28 genes. Thus, it presents cancer researchers many targets for cancer-killing drugs. And because ras is involved in about 30 percent of human cancers, discovery of the house-of-cards pathway could lead to treatments for more than one type of cancer.

In experiments published in the October 25, 2007, issue of Nature, Green and his colleagues reported their dissection of one of ras's premier talents: its ability to switch off the cell's self-destruct mechanism, called apoptosis. This process rids the body of damaged or unneeded cells.

Specifically, Green wanted to understand how ras silences a gene called Fas, one of the cell's master kill-switches. Fas is a tumor suppressor gene, poised to trigger apoptosis. It is held in check only because its activating region is shrouded in molecules called methyl groups. Such control is called epigenetic because it involves modifying the protective packaging that surrounds genes within chromosomes. This modification can regulate whether the genes are switched on or silenced. Epigenetic control is distinct from genetic control, which uses regulatory switches embedded in the DNA sequence of the genes. Specifically, in this case, ras silences Fas by recruiting other molecules to smother it in methyl groups, a state called “hypermethylation.”

Researchers had advanced two theories about the mechanism by which such silencing takes place: The “random” theory held that addition of methyl groups is random and that the resulting cells have a growth advantage that enables them to proliferate. By contrast, the “instructive” theory held that ras uses a specific mechanism to epigenetically silence the tumor suppressor gene.

Art: Shout

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