Pull one strand of a spider’s web, and the rest of the silken construction will flex and shake with the strain. The same effect can be seen in the network of genes involved with cancer, says Kunxin Luo, a Berkeley professor of cell and developmental biology. Her work with the protein TGF-beta is laying bare pathways to some of cancer’s biggest culprits.

The Jekyll and Hyde Act of Oncogenes

by Kathleen M. Wong

Kunxin Luo is also a cell biologist with Lawrence Berkeley National Laboratory’s Life Sciences Division. Photo courtesy LBNL

In cancer, the protein known as TGF-beta is both a blessing and a curse. Among cells just beginning to turn malignant, it acts as a tumor suppressor, inhibiting their growth. But among later stage cancers, this protein that also regulates wound healing and cellular growth becomes a tumor promoter that provokes metastasis.

How can a single molecule trigger exert such contradictory effects? In fact, genes with such dual roles in cancer may be the rule rather than the exception. “When you inhibit a tumor suppressor, you encourage cancer,” explains Kunxin Luo, “That poses a challenge for treatment.”

A Berkeley professor of cell and developmental biology, Luo studies the cellular signaling pathways turned on by TGF-beta. From the moment this protein binds to a cell, it triggers a number of biochemical changes that have a fundamental effect on cancer protection and promotion. “We study in TFG-beta the complexity of these regulatory processes to develop better means of treating cancer,” Luo says.

TGF-beta receptors interact with intracellular molecules called Smad. When Luo went fishing for molecules that bind to Smad, she netted two proteins of particular note: Ski (named for the Sloan-Kettering Institute, where it was first identified) and its relative, SnoN (Ski-related novel protein N). “They seem to be gold mines of new effects,” Luo says.

Since their discovery some 25 years ago, both have been considered cancer-promoting, or oncogenic. They inhibit TGF-beta’s tumor suppressing qualities, and are expressed in substantial amounts by breast, ovarian, and lung cancer cell lines. Yet when Luo tweaked normal cells to overproduce SnoN and Ski, these changes were insufficient to turn cells malignant.

Realizing the story must be more complicated, Luo shifted gears. She made a version of SnoN unable to interact with Smad, and inserted it into mice. The mutant mice possessed an odd combination of traits: premature aging, cancer resistance, and embryonic brain and blood vessel defects. Some of these features likely stem from a severed connection to TGF-beta activity.

TGF-beta communicates with the cells via receptors and several signaling molecules such as Smad and Sno. These pathways can promote cell proliferation and cancer, or cause premature aging (senescence), inhibiting tumor formation. Image courtesy LBNL

In culture, Luo found, cells from the mutant mice divided only six times rather than the usual ten. This explained the source of the accelerated aging. The cells also churned out high levels of a potent tumor suppressor called p53, which produced cancer resistance.

This was the discovery Luo had been hoping for. It explained how SnoN could both hasten cancer, by inactivating TGF-beta, and check cancer growth, via p53. “What we end up with is a molecule with two different functions,” Luo says.

The finding also helps illuminate the route to malignancy. To develop into full-blown cancer, cells must sustain multiple mutations to overcome the body’s many anti-cancer mechanisms. Luo thinks SnoN serves as one such early-stage defense.

Cells that have just started to become cancerous likely upregulate SnoN, which in turn activates p53. As in the mutant mice, p53 limits the spread of cancer. “The goal of cancers is to get rid of this pathway. And in 60 percent of human cancers, one of those mutations is in p53,” Luo says.

For a cancer cell, mutations that shut down p53 are more advantageous than those that eliminate SnoN. With SnoN intact, or even upregulated, cancers can inhibit TGF-beta’s anti-tumorigenic activity.

TGF-beta receptors interact with signaling molecules called Smad. This model depicts Smad4 interacting with the Ski protein, which in turn affects gene expression in the cell. Image courtesy Kunxin Luo

“We’re finding that such pro- and anti-cancer pathways are not linear; they are networks where many molecules regulate each other. If we want to develop better cancer therapies, we need to know more about these networks that we can selectively inhibit one pathway and not touch the other,” Luo says.

The fact that many oncogenes operate in networks highlights a potential advantage of personalized medicine. Genetic tests that reveal which oncogenes are mutated in a given cancer could identify which pathways are involved and therefore which drugs might be most effective in each case. In other words, scientists could learn how to harness the Jekyll and Hyde tendencies of oncogenes like TGF-beta for healing rather than harm.

Related Web Sites

• Kunxin Luo, Department of Molecular and Cell Biology
• “Did you ever wonder….what makes a normal cell turn cancerous?” Scientist profile, Lawrence Berkeley National Laboratory