Mixed Signals
Ebrahim Zandi is pursing an understanding of the precise steps by which a signal is passed from outside a cell to its nucleus in order to turn specific genes on or off.
by Lori Oliwenstein
Ebrahim Zandi, Ph.D., is always running headlong toward a goal. That goal may have been a more tangible one in his native Iran-where he played professional soccer-than it is in his laboratory at the USC/Norris Comprehensive Cancer Center, but that makes it no less compelling.
These days, Zandi's playing field is the Department of Molecular Microbiology and Immunology at USC/Norris, where he recently joined the faculty as an assistant professor. And the goal he is now pursing with single-minded intensity is a thorough understanding of the precise steps by which a signal is passed from outside a cell to its nucleus in order to turn specific genes on or off.
Genes rely on signals for their marching orders. For example, a gene that causes a cell to divide in two will never set that process in motion unless turned on by an outside stimulus. Once turned on, it will continue to promote proliferation until another signal turns it off. Most of the signals the genes rely on come from molecules outside the cell, however, and many of those molecules are unable to pierce the cell's sturdy lipid membrane. The only way such a molecule can get its message to the nucleus is by fitting into a receptor on the cell's surface and then prompting a cascade of chemicals called signaling molecules and transcription factors to carry the message along. That cascade is called signal transduction.
Many cancers are a case of signal transduction gone wrong. "Cell death is a natural process in the body-normal cells die when they are signaled to do so," says Zandi. "In cancer cells, this programmed cell death is inhibited. Somehow, the cancer cells are producing proteins that stop the cellular death machinery from being activated."
As it turns out, this is not a passive process: A cancer cell, it seems, actively produces what Zandi calls "anti-death factors," which stop the death signal from turning on the death machinery. The way cancer cells produce anti-death factors is by taking advantage of nuclear factor kappa B (NFKB). Under normal circumstances, NFKB's role in the body is to help set up the process of inflammation. But while NFKB's role in the inflammatory process is transitory-it turns on and then turns off again, usually within 30 minutes to an hour-cancer cells have found some way to activate it continuously. And once it is on, it is the consummate cell death-blocker.
Because NFKB is such an important transcription factor, Zandi has been focusing on just how it is controlled. "We need to identify every building block in the pathway and find out how they interact with and regulate each other," he says. "It's the only way to understand how something goes wrong."
Finding NFKB's regulator turned out to be a major undertaking. But in 1997, while still at the University of California at San Diego, Zandi and his colleagues tracked down a protein called I Kappa B Kinase (IKK). "IKK was considered the Holy Grail of signal transduction," he says. "It was a big finding."
Now, here at the USC/Norris, Zandi and his colleagues are looking more closely at IKK and its role in cancer. "We're trying to determine if IKK is activated in as many kinds of cancers as we can test," he explains. "If it's a major player in a number of cancers, it might make a good therapeutic target."
Whatever they are working on, you can be sure Ebrahim Zandi and his researchers will be focused on the goal. "In science, as in sports," he says, "it takes the whole team working together to win."