Proteasomal Degradation Thwarts the Apoptotic Efforts of Bax-Beta Protein

In healthy cells, the outer membranes of the mitochondria display the apoptosis inhibiting protein Bcl-2. Internal damage to the cell causes a related protein, Bax, to migrate to the surface of the mitochondrion where it inhibits the protective effect of Bcl-2 and inserts itself into the outer mitochondrial membrane. It then pokes holes in the membrane, which allows cytochrome c to leak out. The released cytochrome c binds to the protein Apaf-1 (apoptotic protease activating factor-1). The Apaf-1-cytochrome c complexes aggregate to form apoptosomes that bind to and activate the protease caspase-9. Caspase-9 cleaves and, in so doing, activates other caspases (caspase-3 and -7). The activation of these "executioner" caspases creates an expanding cascade of proteolytic activity, which leads to digestion of structural proteins in the cytoplasm, degradation of chromosomal DNA, and phagocytosis of the cell.

Evidence form RNA data convinced investigators at the Institute of Molecular and Cell Biology (Singapore) that additional and possibly more potent apoptotic proteins should coexist with Bax-alpha. By inhibiting the action of the cell's primary protein digesting organelle, the proteasome, they were able to demonstrate the existence of a second Bax protein, Bax-beta. They reported in the January 16, 2009, issue of the journal Molecular Cell that Bax-beta was normally rapidly degraded and kept at low levels. However, when it was not degraded, it was profoundly apoptotic on its own and worked in concert with Bax-alpha.

"Our research findings reveal that Bax-beta protein levels are normally kept at essentially undetectable levels in healthy cells by the protein degradation machine in cells known as proteasomes," said senior author Dr. Victor C. Yu, an associate professor at the Institute of Molecular and Cell Biology. "This is exciting - if the proteasome-mediated degradation of Bax-beta could be inhibited specifically in cancer cells, it could cause the harmful cancer cells to go through apoptosis."

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