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'Reaper' protein strikes at mitochondria to kill cells

Date:
October 26, 2010
Source:
Rockefeller University
Summary:
Many billions of cells in the human body kill themselves every day, as the old and decrepit make way for the new and healthy. This process of programmed cell death, called apoptosis, is crucial in early development and in the routine maintenance of life. New research indicates a technique that could allow for highly efficient, targeted killing of problematic cells such as those that drive the uncontrolled growth of tumors.

Normal eye on the left. Eye on the right is almost completely destroyed by apoptosis.
Credit: Image courtesy of Rockefeller University

Our cells live ever on the verge of suicide, requiring the close attention of a team of molecules to prevent the cells from pulling the trigger. This self-destructive tendency can be a very good thing, as when dangerous precancerous cells are permitted to kill themselves, but it can also go horribly wrong, destroying brain cells that store memories, for instance.

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Rockefeller University scientists are parsing this perilous arrangement in ever finer detail in hopes that understanding the basic mechanisms of programmed cell death, or apoptosis, will enable them eventually to manipulate the process to kill the cells we want to kill and protect the ones we don't.

In experiments published last month in the Journal of Cell Biology, researchers led by postdoctoral associate Cristinel Sandu in Hermann Steller's Strang Laboratory of Apoptosis and Cancer Biology drilled down on a protein aptly named Reaper, which was first described in a 1994 paper by Steller in Science. Under the right conditions, Reaper interferes with molecules called inhibitor of apoptosis proteins (IAPs), which prevent the cell from irrevocably initiating its autodestruct sequence. By inhibiting these inhibitors, Reaper essentially takes the brakes off the process of apoptosis, pronouncing a cell's death sentence. Other molecules called caspases then carry that sentence out.

"Like the grim reaper, Reaper is an announcer of death, but not the executioner," says Steller, who is also a Howard Hughes Medical Institute investigator. "It's like the key that starts the engine."

Reaper and the other Drosophila IAP antagonists Hid and Grim are known to trigger apoptosis in flies, and related proteins serve a similar function in humans and other mammals. But exactly how and where Reaper initiates apoptosis has not been well understood. Sandu and colleagues bred genetically modified strains of flies that expressed variations on the Reaper protein specifically in flies' eyes. This allowed them to assess the contribution of individual protein motifs to Reaper's apoptosis inducing powers, and what they found was that a particular helical domain was crucial for the formation of Reaper complexes, and could be modified to be even more powerful than the regular protein. The more deadly Reaper variants were obvious by the damage caused to the flies' eyes.

In a series of biochemical experiments, the researchers also found that Reaper must travel to the mitochondria, the cell's energy factories, to effectively deliver its death sentence, and that to get there, it must hitch a ride on the Hid protein, with which it interacts. By tagging Hid and Reaper fluorescently, Sandu could visualize Hid and Reaper acting in a complex and gathering at the membrane of the mitochondria. When Reaper was engineered to go directly to the mitochondrial membrane, it resulted in a molecule that is far superior at triggering cell death than regular Reaper. Further experiments suggested that in a complex with Hid, Reaper is protected from degradation as the cells began to die.

"So now we have Hid and Reaper working very closely together," Sandu says. "And the localization to the mitochondria is crucial to the initiation of apoptosis." Drugs that mimic a small part of the function of Reaper are already in clinical trials. The discovery of a way to make Reaper a much better killer, namely by targeting it directly to the mitochondria, provides new avenues to explore for improving cancer therapies. "Adding this element that takes Reaper directly to the mitochondria is not something people would have thought of before this," Steller says.


Story Source:

The above story is based on materials provided by Rockefeller University. Note: Materials may be edited for content and length.


Journal Reference:

  1. C. Sandu, H. D. Ryoo, H. Steller. Drosophila IAP antagonists form multimeric complexes to promote cell death. The Journal of Cell Biology, 2010; 190 (6): 1039 DOI: 10.1083/jcb.201004086

Cite This Page:

Rockefeller University. "'Reaper' protein strikes at mitochondria to kill cells." ScienceDaily. ScienceDaily, 26 October 2010. <www.sciencedaily.com/releases/2010/10/101020131710.htm>.
Rockefeller University. (2010, October 26). 'Reaper' protein strikes at mitochondria to kill cells. ScienceDaily. Retrieved November 24, 2014 from www.sciencedaily.com/releases/2010/10/101020131710.htm
Rockefeller University. "'Reaper' protein strikes at mitochondria to kill cells." ScienceDaily. www.sciencedaily.com/releases/2010/10/101020131710.htm (accessed November 24, 2014).

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