Sci. Aging Knowl. Environ., 17 March 2004
Going Ku Ku on Bax
Extrachemical affair shatters union, provokes suicide
When dramatic machinations part Shakespearean lovers, the play usually comes to a tragic end. But when biological forces divide a pair of proteins in cancer-prone cells, the show goes on for the lucky organism. Now, researchers have discovered the molecular intrigue that keeps the curtain up: Troubled cells chemically modify a particular protein and free its partner, which incites suicide. The results suggest ways to improve cancer therapies.
When cells start turning cancerous, an internal program usually drives them to kill themselves. A protein called Bax points them down this road by punching holes in mitochondria, the cell's energy factories. Last year, scientists found that a DNA-repair protein called Ku70 normally grabs Bax and prevents suicide. No one knew how Bax escaped from Ku70's clutches, but scientists had a clue: Mice that are engineered to lack a protein that normally sticks acetyl groups onto proteins are prone to cancer because their cells can't off themselves. Other work further implicated these chemical groups in malignancy: Drugs that keep acetyl groups on proteins boost the power of anticancer therapies. Cohen and colleagues identified lysines in Ku70 that might sport the chemical embellishments, and they wanted to determine whether Ku70 picks up acetyl groups that turn the protein deadly.
Using a variety of biochemical tests, the scientists determined that Ku70 in cells gets decorated at eight spots; two of these are near the part of the protein that grabs Bax. The team then engineered cells in culture to overproduce Ku70, Bax, or both. As expected from previous work, cells that contained Bax alone committed suicide, but those that made surplus Ku70 in addition escaped that fate. Next, the researchers added a chemical called nicotinamide that encourages the attachment of acetyl groups to proteins. This chemical obliterated Ku70's protective effect, indicating that the adornments prompt the protein to liberate Bax.
The researchers then replaced the two candidate lysines in Ku70 with an amino acid whose shape resembles an acetyl-topped lysine. Neither of the two resulting Ku70s prevented suicide, presumably because the acetyl-like protrusions interfere with their ability to hug Bax. Finally, the team found that in test tubes, nicotinamide prevented normal Ku70 and Bax from embracing. Together, these results indicate that tagging Ku70 with acetyl groups disrupts its hold on Bax, which can then induce suicide.
By revealing how Ku70 emancipates Bax, the work offers new insight into the therapy-enhancing effects of compounds that maintain proteins' acetyl groups. "We had no way of knowing how [drugs that protect acetylation] work in synergy with anticancer therapies," says cancer biologist Ricky Johnstone of the Peter MacCallum Cancer Institute in East Melbourne, Australia. "This work might provide the mechanism." Treatments that increase the pool of free Bax in cells, by adding acetyl groups to Ku70 or by other means, could likely improve "a whole range of anticancer therapies." Such a twist in the plot might give cancer patients long intermissions from their disease.
March 17, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150