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Blocking one protein helps cancer cells die of natural causes

January 08, 2003

Researchers have identified a protein fragment that keeps at least one major tumor suppressor gene from preventing cancer like it should. The fragment belongs to a class of proteins known as apoptotic enhancers (ASPP), named for their ability to stimulate programmed cell death, or apoptosis, by the p53 gene.

But a study published in Nature Genetics finds that one member of this group, called iASPP, actually inhibits p53's normal cell killing power. When iASPP levels were reduced in experiments on different cell types, investigators found that the wild-type p53 gene could better suppress tumor cell growth, a strong sign that iASPP acts as a natural impediment to controlling cancer.   

"By all measures, it appears that iASPP plays a crucial role in turning normal cells into cancerous ones," said the study's lead author, Dr. Xin Lu, who is with the Ludwig Institute for Cancer Research, London St. Mary's Branch, and a professor at Imperial College London. "We can now target iASPP in further studies to potentially destroy tumors that express this gene."   

These results add to a growing list of attempts to attack cancer through the p53 corridor, one of the major genetic figures in controlling tumor growth. In a remarkably high number of cancers, the p53 gene is mutated and fails to work, allowing tumors to spread. The normal, or so-called wild-type versions of p53, are often disabled in cancer as well. For instance, the wild-type p53 gene fails to suppress tumors in 70% of breast cancers.

An intriguing possibility for this poor success rate could be a mishap in the ASPP family. Like the poisonous snake asp that causes Cleopatra to die, ASPP enforces programmed cell death for wild-type p53: the three related proteins attach themselves to the tumor suppressor gene, controlling the on and off switch that signals malignant cells to essentially commit suicide. Two of the proteins (ASPP1 and ASPP2) stimulate the gene's suicidal demands, but now researchers are seeing an opposite effect in the third.

When iASPP levels were lowered in worm and human cell lines, Dr. Lu's team found that p53 killed off more cells. Higher iASPP levels, on the other hand, caused the cells to become more resistant to the destructive effects of ultraviolet rays and the chemotherapy drug, cisplatin. Using specialized genetic techniques to block this protein, the researchers found that inhibiting iASPP could enhance the potential tumor suppressing abilities of p53 by as much as five-fold.

"The amazing thing is that iASPP is not only an opponent of p53, but it must be a very important one since it has been doing the same job for millions of years," said Dr Lu. "These three ASPP proteins act as the Yin and Yang modulators of p53."

Ludwig Institute for Cancer Research