Direct Apoptotic Effect Clarified
By Anthony J. Brown, MD
NEW YORK (Reuters Health) Apr 12 - The well-known tumor suppressor protein p53 seems to directly promote apoptosis by interacting with a mitochondrial protein called Bak, new research suggests. Further understanding of this interaction could lead to molecular mimics of p53 with potential as anti-cancer agents.
Although p53 has been primarily characterized as a transcription factor, "there has been evidence that it may promote apoptosis" through other, more direct routes as well, senior author Dr. Donna L. George, from the University of Pennsylvania School of Medicine in Philadelphia, told Reuters Health. In particular, "p53 seems to have a direct signaling role at the mitochondria."
In the current study, reported in the April 11th online issue of Nature Cell Biology, Dr. George's team looked at the interaction between p53 and Bak, a B-family protein with pro-apoptotic effects.
"Previously, it was shown that Bak undergoes oligomerization when it is promoting apoptosis," Dr. George noted. "So, we were interested in knowing whether p53 was capable of inducing this oligomerization in Bak."
The researchers found that p53 did, in fact, cause oligomerization of Bak, resulting in the release of cytochrome c from mitochondria--an event that leads to apoptosis.
So what stops Bak from promoting apoptosis under normal circumstances?
"In normal cells, in the absence of stress, Bak isn't undergoing oligomerization and causing the mitochondria to release cytochrome c," Dr. George said. "We identified a protein called Mcl1 that interacts with Bak and prevents it from causing apoptosis. Also, we found that when p53 binds to Bak it disrupts the interaction with Mcl1."
Further studies are needed to clarify the extent to which p53's mitochondrial effects contribute to the overall apoptotic response, Dr. George noted. In designing p53 mimetics, "it is important to know whether the mitochondrial effects alone are sufficient for apoptosis or if they must work in concert with the transcription factor effects."
Nat Cell Biol 2004;April 11th online issue:000-000.
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