on the braking

Weizmann Institute scientists have discovered: a group of genes that suppress the processes of cell division, and prevent the development of a cancerous tumor

 
From the right: Prof. Eitan Domani, Ido Amit and Prof. Yosef Yordan. Chain of events
Cancer cells differ from normal cells, among other things, in their division and reproduction processes. When a normal cell receives an external signal commanding it to divide and multiply, it obeys the command, activating an efficient "brake system", which limits the reproduction process, and after several cycles of division returns the cell to a resting state. In this way the body protects itself from uncontrolled cell division. In the cancer cell, on the other hand, the brake system is damaged, which causes the uncontrolled proliferation of the cell, and the formation of a cancer tumor. Weizmann Institute scientists studied the "brake system", and discovered some of the genes that activate it.
According to the research findings, recently published in the scientific journal Nature Genetics, abnormal activity of these genes characterizes different types of cancer, and is related to the degree of violence of the cancer. These insights may help, in the future, to develop ways and methods to repair the damaged brake system, with the aim of stopping the cancer process.
In the first step, the scientists sought to map the gene system activated in a normal cell, in response to receiving an order instructing it to divide. The signaling reaches the cells from the outside, through a certain hormone, called "growth factor", which activates a chain of events inside the cell. As a result, the cell produces certain proteins, according to the DNA sequence of the gene that codes them. In recent years it became clear that this hormone is involved in the development of various types of cancer, but
In the current study, the scientists wanted to know which genes, exactly, are responsible for activating the cell's brake system. To find an answer to this question, the scientists were required to scan a huge amount of genes, collect precise quantitative data about their activity, and identify their activity patterns. In order to deal with this wide-ranging task, scientists from different fields of research collaborated: Prof. Yosef Yordan from the Department of Biological Control, Prof. Eitan Domani from the Department
for the physics of complex systems, Prof. Uri Alon from the Department of Molecular Cell Biology, and Dr. Eran Segal from the Department of Applied Mathematics and Computer Science, all from the Weizmann Institute of Science. Together with you worked Prof. Gideon Ravavi from the Sheba Sheba Medical Center in Tel Hashomer, and researchers at the Anderson Cancer Research Center in Houston, Texas. The use of research methods from the field of physics, mathematics and computer science for the purpose of organizing and analyzing biological information has been gaining momentum in recent years, especially in studies of this kind, where scientists are dealing with huge amounts of information. Weizmann Institute scientists were among the first to recognize the importance of breaking through the boundaries between traditional scientific fields, and the Weizmann Institute of Science is currently one of the leading institutions in the world in this type of multidisciplinary research. The collaboration brought surprising results: it turned out that following the binding of the growth factor to the cell, several "waves" of gene activity occur in the cell. Different groups of genes are turned on and "turned off" in different time frames. The first wave included a few genes, whose activity increases for 20 to 40 minutes after exposure to the growth factor. These genes are mainly responsible for the "positive" reaction to the growth factor, that is, they cause the cell to divide. Conversely, in the four later waves, in the range of 240-40 minutes, genes responsible for turning off the reaction and stopping division were activated. Later, the researchers focused on a number of "turn off genes" from the later waves, with the assumption that these genes - which are active in normal cells - can also function as tumor suppressors, and stop the uncontrolled division, which is characteristic of cancer cells.
To prove that the genes in the later waves do function as "Maccabi genes", the researchers looked for genes whose proteins they produce are capable of inhibiting the activity of other genes (whose activity causes the cell to divide), through a direct link to them. In a large-scale study, about 50 suppressor genes, or growth inhibitors, were found, the proteins they produce bind to the genes of the first wave - and suppress them. 

 
 
Research student Tal Shay

Another protein created in one of the later waves stops the response to the growth factor in another way: it simply "kills the messenger" (messenger RNA molecules). These molecules transfer the genetic information from the gene in the cell nucleus to the cell's protein production system, which then produces the protein that causes the cell to divide. The quencher protein binds to the messenger RNA, directs it to degradation, thus sabotaging the activity process of the gene that causes division.
In tests performed on ovarian cancer patients, the scientists discovered that there is a correlation between inactivity, or a low level of activity, of the Maccabi genes they discovered, and the patients' low life expectancy. A low level of activity of these genes was found to be related to other clinical indicators of the severity of the disease. These findings can lead to the development of a personal genetic profile, which describes the level of activity of the various genes that stop the processes of cell growth and division, in each patient's body. Such a personal genetic profile will precisely define the disruption that caused the cancer, thus allowing targeted and effective treatment to be adjusted according to the genetic characteristics of each patient. The genetic profile will also help in predicting the degree of violence of the cancerous tumor. Identifying the factors that prevent the Maccabian gardens from operating properly, such as for example
Genetic mutations, and the development of methods for the proper activation of these genes, may, in the future, help develop ways to prevent the uncontrolled division of cells, and curb the cancer process. The research students Ido Amit, Ami Tzari, Gabi Tersik and Menachem Katz, from the research group of Prof. Yosef Yordan in the Department of Biological Control, Tal Shay from the research group of Prof. Eitan Domani in the Department of Physics of Complex Systems, Yasmin Yaakov-Hirsh and Ninette Amarilio from the group of Prof. Gideon Rafi at the Sheba Medical Center and the School of Medicine at Tel Aviv University, Nora Weissman from Sigma-Aldrich Israel, and the research group of Prof. Gordon B. Mills of the Anderson Cancer Center in Houston, Texas. 
Activity of various genes following exposure to a growth factor. An increase in the activity of about 400 genes was found, starting from the moment the growth factor was administered (time 0). Increased activity of the genes is expressed in red colors. Little activity is expressed in blue colors. It can be seen that the increase in activity occurs in several waves: a small group of genes reaches the peak of activity about 20 minutes after the administration of the growth factor, and several groups of genes reach the peak of activity in longer periods of time (480-40 minutes).