Woody Allen once said, "It's not that I'm afraid to die. I just don't want to be there when it happens!"
Perhaps he was unaware of it, but if we're lucky, we all actually "die" a little every day. A growing body of scientific evidence is proving what philosophers and artists have preached for millennia -- that a healthful life is dependent on, driven forward, by death.
Cells contain built-in suicide mechanisms. Known as apoptosis, or programmed cell death, 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.
Apoptosis failure can be deadly. Cell mutation occurs regularly due to environmental factors such as ultraviolet radiation and chemical toxins, as well as natural cell processes. If left unchecked, the damaged cells continue to proliferate, often leading to life-threatening diseases, such as cancer.
Prof. Yosef Shaul of the Weizmann Institute's Molecular Genetics Department has deciphered part of the cellular events underlying this pivotal defense mechanism. Published in Nature, his findings provide important insights into cancer pathologies and their potential cures.
"The emergency pathway is designed to reverse or mitigate mutation-induced damage," explains Shaul. "It's an intricate check-and-balance system controlled by a tightly orchestrated team of genes and their respective proteins. Interacting within a rigid, cascading 'If, Then, Else' environment characteristic of computer programming, the proteins initially attempt to repair the DNA. But if unsuccessful, they command the cell to self-destruct. In the third and worst-case scenario, both DNA repair and apoptosis fail, and disease usually ensues.
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 that, when mutated, can act as an oncogene, a gene that causes cancer. For instance, 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 decided to examine why c-Abl breakdown results in cancer. Specifically, what is its role in safeguarding the cell?
The Weizmann Institute team found that irradiation-induced DNA damage activates c-Abl, which subsequently recruits p73, another key regulating protein. If earlier attempts at cell repair fail, the interplay between these proteins leads to cell death. "The likelihood of tumor formation increases significantly if the function of either protein is flawed," Shaul explains. "Likewise, most cancer therapies depend on this cell repair mechanism. The object of chemotherapy and radiation is to activate the protein teamwork that causes damaged, cancerous cells to self-destruct."
Being able to pin down 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 to individual pathologies.