A "family" of apoptosis-regulating proteins contains both pro-death (including BAK, BIM and BID) and pro-survival members. One pro-survival molecule is called BCL-2, named for the disease it causes B-Cell lymphoma when it is overexpressed in white blood cells, allowing them to accumulate abnormally. BCL-2 performs much of its pro-survival function by binding and sequestering pro-death molecules, preventing them from transmitting a pro-death signal.

Some pro- and anti-apoptosis molecules are generally found on the membrane forming the outside of mitochondria. These are tiny mini-organs in cells that provide energy but also contain a substance that kills cells if it is released into the cell's interior.

One of the crucial signals for apoptosis is a protein called BAK, which resides in an inactive form on the mitochrondrial membrane. When other pro-death signals activate it, BAK changes shape and opens holes in the membrane that release the lethal cytochrome c from the mitochondrion. The pro-survival signal BCL-2 also is found on the membrane, and its function is to keep BAK inactive, preventing cell suicide.

Letai, who is also an instructor in medicine at Harvard Medical School, and his colleagues looked closely at the life-death process by isolating living mitochondria from cells and manipulating them in the laboratory. They devised tests that could show whether molecules like BAK were "activated" that is, carrying out their pro-death function.

BAK can be set into motion in two ways: pro-death signal proteins BID or BIM can bind to BAK, or other pro-death proteins BAD and BIK can flood BCL-2, keeping that pro-survival protein occupied so that BID proteins can evade BCL-2 and bind to BAK, turning it on.'"/>

Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
13-Sep-2002