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 that the discovery of p73 and later p63, both members of the family of p53 tumor suppressors, took the scientific community by surprise."
Nevertheless, Shaul's team was unable to demonstrate a connection between c-Abl and p53, which meant they had to look elsewhere. And their decision to examine c-Abl's interaction with p73 (following its discovery) proved correct.
Phosphate 'Fuel'
Similar to fuel-dependent mobility, the Weizmann team found that the interplay between c-Abl and p73 is phosphate-dependent. Irradiation activates c-Abl (through both phosphate binding and other mechanisms), and c-Abl subsequently activates p73 by phoshorylating it. "Our research suggests that both p73 and c-Abl influence whether a cell becomes cancerous following DNA damage," Shaul explains. "If the function of either of these proteins is flawed, through mutation or impaired phosphorylation, the likelihood of tumor formation increases significantly." Shaul is currently studying these conditions using 'knock-out' mice in which the cell tumor suppression genes have been cancelled.
According to Shaul, the ability to pinpoint the precise point of damage along the pathway leading to DNA repair, cell death or tumor formation, could enhance future cancer therapies.
"Understanding the origin of disease in each patient may prove vital to determining the most effective form of therapy, 'tailored' according to individual patient pathologies. Potential treatments would include radiation, drug therapy or eventually even gene therapy, in which the damaged gene is replaced by a functioning counterpart," says Shaul.
Prof. Shaul holds the Oscar and Emma Getz professional chair. This study was supported by the Burstein Family Foundation.
The Weizmann Institute of Science, in Rehovot, Israel, is one of the world's foremost centers of scientific research and graduate study. Its 2,500 scientists, students, technicians and engineers pursue basic research in the quest for knowledge and the enhancement of humanity. New ways of fighting disease and hunger, protecting the environment, and harnessing alternative sources of energy are high priorities at Weizmann.
Journal
Nature