Cooperative Action Of Two Proteins Causes Damaged Cells To "Self-Destruct"
- Date:
- December 21, 1999
- Source:
- Weizmann Institute
- Summary:
- Researchers at the Weizmann Institute of Science have recently deciphered part of the cellular events underlying apoptosis - programmed cell death. Their findings, published in Nature earlier this summer, provide important insights into cancer pathologies and their potential cures.
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REHOVOT, Israel -- December 20, 1999 -- Researchers at the Weizmann Institute of Science have recently deciphered part of the cellular events underlying apoptosis - programmed cell death. Their findings, published in Nature earlier this summer, provide important insights into cancer pathologies and their potential cures.
It is known that all cells contain a built-in suicide mechanism. This process is vital to normal embryonic development and tissue maintenance. It is the body's means of ridding itself of damaged or surplus cells.
Failure of the apoptosis or suicide mechanism can be deadly. Cell mutations occur regularly in every organism due to environmental factors, such as ultraviolet radiation and chemical toxins, as well as natural cell processes. If left unchecked, the damaged cells will continue to proliferate, often leading to life-threatening diseases, such as cancer.
This "emergency" suicide pathway is designed to reverse or mitigate mutation induced damage, explains Prof. Yosef Shaul of Weizmann's Molecular Genetics Department. It is an intricate check and balance system controlled by a tightly orchestrated team of genes and their respective proteins. These genes interact with each other in an environment characteristic of computer programming, where they respond to If, Then, Else signals concerning cellular functioning. The protein products of these genes will initially attempt to repair the damaged DNA. If they are unsuccessful, they command the cell to "self-destruct." In the third, and worst case scenario, both DNA repair and apoptosis fail, and the result is usually the growth of a tumor.
Yet who are these protein "players", and most importantly, how do they interact? This is what Shaul and colleagues, Prof. Moshe Oren, and Drs. Reuven Agami and Giovanni Blandino, set out to understand.
They began with c-Abl - a major regulator of cell growth which, when mutated, can act as an oncogene - a gene that causes cancer. Earlier research has linked c-Abl malfunctioning to cancer. More than 90 percent of patients with chronic myeloid leukemia have a unique abnormality known as the Philadelphia chromosome, characterized by c-Abl mutations. Shaul therefore decided to examine what c-Abl's role is in safeguarding the cell.
A Family of Tumor Suppressors
The Weizmann team found that irradiation-induced DNA damage activates c-Abl, which subsequently 'recruits' p73, another key regulating protein. The interplay between c-Abl and p73 leads to cell death.
"p73 was a surprise," admits Shaul. "Initially, we believed that c-Abl's most likely cell repair partner would be p53, which until 1997 was perceived as the only tumor suppressor of its kind. Indeed, over 50 percent of all cancer patients show p53 mutations. This is one of the reasons t
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