"For the first time, we have shown that another protein (Reaper) enhances the activity of a ubiquitinating ligase (DIAP1)," says Ryoo. "The rate of DIAP1 ubiquitination is not constant, but is actively stimulated in cells that are fated to die."

Gas and break model of cell death

The primary executioners in programmed cell death are proteins called caspases. These are the proteins that wreak havoc on a cell and eventually kill it. Other proteins, which Steller calls the "gas," signal a cell to activate caspases when its time to die.

But in a healthy cell the presence of active caspases is not enough to induce cell death; these deadly molecules are kept on a tight leash by the IAPs, for "Inhibitors of Apoptosis Proteins," or, as Steller calls them, "the breaks on death."

Consequently, before cell death can occur these "brakes" must be released. This is the job of the Reaper family of proteins, which includes Reaper, Hid and Grim, and which Steller discovered in 1994.

"Reaper is like a molecular switch that triggers cell death by inactivating a "pro-life" IAP protein, DIAP1. In living cells, DIAP1 is abundant and prevents apoptosis," says Ryoo. "But in cells that are doomed to die, Reaper inactivates DIAP1, which then leads to the release of the caspases."

"Reaper, Hid and Grim are like the keys that unlock the chains of deadly caspases," adds Steller.

But, until now, scientists did not know the precise mechanism by which the Reaper family of proteins inactivated the IAPs, or, in other words, released the breaks on death.

The new Rockefeller research is the first to show that Reaper, but not Hid, inactivates DIAP1 by triggering its disapperance. In the past, scientists could not easily study the effects of Reaper in dev
'"/>

Contact: Whitney Clavin
clavinw@mail.rockefeller.edu
212-327-7250
Rockefeller University
20-May-2002