Sci. Aging Knowl. Environ., 17 November 2004
Vol. 2004, Issue 46, p. nf102
[DOI: 10.1126/sageke.2004.46.nf102]


Ironing Out Cell Death

Metal-grabbing enzyme saves suicidal cells

Mitch Leslie

Like a governor giving a pardon, the molecule NF-{kappa}B spares cells condemned to death. New research reveals that the protein delivers its stay of execution by enlisting an iron-absorbing protein, which short-circuits a death-promoting pathway. The work could help researchers devise better treatments for conditions in which cells ignore suicide directives, including cancer and rheumatoid arthritis.

One situation in which a cell's fate hinges on NF-{kappa}B is during inflammation. Tumor necrosis factor {alpha} (TNF-{alpha}) spurs injured or infected cells to kill themselves through a process known as apoptosis. NF-{kappa}B, in contrast, keeps cells alive. Researchers have a hazy understanding of how NF-{kappa}B countermands TNF-{alpha}'s death decree. Cells destined to perish amass reactive oxygen species (ROS), corrosive byproducts of metabolism (see "The Two Faces of Oxygen"). Previous work suggested that NF-{kappa}B squelches ROS, thus blocking a death-inducing pathway called JNK, which indirectly rouses cell-killing enzymes. Molecular biologist Guido Franzoso of the University of Chicago, Illinois, and colleagues wanted to nail down the mechanism.

When the researchers splashed cells lacking NF-{kappa}B with TNF-{alpha}, ROS accumulated, and the cells also died in droves. Treating them with antioxidants, however, boosted their survival rate. Moreover, restoring NF-{kappa}B chopped ROS concentrations, bolstering the case that NF-{kappa}B salvages suicidal cells by quashing ROS. The researchers then sought molecules that do NF-{kappa}B's bidding. They used viruses to spirit different sets of genes into cells missing NF-{kappa}B. Many cells expired, but some persisted. From the survivors, the researchers compiled a list of potentially protective genes and searched it for any known ROS inhibitor that NF-{kappa}B controls. One such molecule was ferritin heavy chain, a protein that locks away cellular iron. Its involvement makes sense, says Franzoso, because cells need iron to produce ROS. To confirm that ferritin spurs survival, the team shuttled extra copies of the ferritin gene into NF-{kappa}B-lacking cells. They were more than twice as likely to live through a dose of TNF-{alpha} as were cells that received no supplementary genes. When the scientists instead trimmed ferritin production in normal cells, more than four times as many cells died in response to TNF-{alpha}, compared with controls. Overall, the work suggests that NF-{kappa}B prevents cell suicide by activating ferritin, which smothers ROS formation. Further experiments suggested that quashing ROS blocks the deadly JNK pathway.

However, saving cells is not always beneficial. In cancer and autoimmune diseases such as rheumatoid arthritis, cells exploit NF-{kappa}B to endure when they shouldn't. The results might help researchers design drugs to shut down NF-{kappa}B in these troublesome cells without inciting broader side effects, such as inhibiting the immune system, Franzoso says.

The work is valuable because it ties together many previous studies on ROS and apoptosis, says molecular biologist Colin Duckett of the University of Michigan, Ann Arbor. "It gives you an additional target" for drugs to soothe inflammation or disrupt cancer, says molecular biologist Sankar Ghosh of Yale University in New Haven, Connecticut. But he cautions that researchers need to confirm ferritin's role by disabling the gene in mice. That work might reveal whether stealing a cell's iron is the key to keeping it alive.

November 17, 2004
  1. C. G. Pham et al., Ferritin heavy chain upregulation by NF-{kappa}B inhibits TNF{alpha}-induced apoptosis by suppressing reactive oxygen species. Cell 119, 529-542 (2004). [CrossRef][Medline]
Citation: M. Leslie, Ironing Out Cell Death. Sci. Aging Knowl. Environ. 2004 (46), nf102 (2004).

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