Life-Yielding Deaths


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Prof. Adi Kimchi: Initiating cell suicide


In almost every movie plot you'll find "good guys" and "bad guys." In our bodies, cancer-related genes can be similarly divided into two such groups - cancer suppressors and cancer promoters. A few years ago Prof. Adi Kimchi of the Weizmann Institute's Molecular Genetics Department uncovered a group of suicide genes that may suppress cancer. In a paper published recently in Nature Cell Biology with graduate student Tal Raveh, she showed that one of these genes - DAP-kinase - plays an important role in a critical cancer-protecting "junction."


Various tumor suppressor genes, including the group of genes discovered by Kimchi, operate by activating a genetic "suicide program" embedded in every cell in the body. When this program is activated, a living cell commits suicide. This phenomenon of self-destruction is called apoptosis - Greek for the falling of leaves. Impaired apoptosis leads to uncontrolled cell proliferation, which can result in tumor formation.


Knockout Genes

Kimchi and her team focused on the biochemical communications network governing apoptosis. In their attempts to identify "hidden" genes that carry out important functions in this network, they developed a new approach, which enables, for the first time, efficient "gene hunting" in mammalian cells. Their method, called TKO (technical knockout) is based on a series of processes involving genetic engineering that randomly disable various genes in cells. When a gene belonging to the "suicide program" network is disabled, that cell, which normally would have committed suicide, is "saved." By observing how "shutting down" a particular gene affects its cell, one can draw conclusions about this gene's role and identity. In this manner scientists can isolate a single gene out of 30,000.


In the past few years, Kimchi and her team have successfully used this method to discover five genes, called DAP (death associated proteins), that are connected to the death-inducing processes in cells. Their development of the TKO method and identification of the DAP genes have received international recognition and won Kimchi several awards, including the prestigious Milstein Prize.


Cancer-Blocking Gene

Recently, the scientists showed that DAP-kinase is responsible for destroying cells that have begun converting into a cancerous state. This is in fact a mechanism for "purging" tissues of cells containing early-stage cancerous abnormalities, such as certain oncogenes (cancer-causing genes). It turns out that the DAP-kinase mode of action includes activating another well-known tumor suppressor gene, p53, along with activating additional factors connected to the cell skeleton. In other words, DAP-kinase is the "trigger" that activates the p53 gene and leads to the destruction of oncogene-containing cells.


A malfunction of DAP-kinase disrupts the suicide program, allowing a cancerous growth to develop. The study's results are supported by the recent detection of DAP-kinase abnormalities in patients with cancers of the lung, breast, head, and neck, as well as in type B cell lymphoma. By improving the mapping of the biochemical "suicide command" chain in cells, the team's findings may aid the development of new cancer drugs.