Together against cancer: mitochondria and tumor suppressor p53
Mitochondrial respiration stopped cancerAlexandra Evstafyeva, Doctor of Chemical Sciences, Leading Researcher at the A. N. Belozersky Research Institute of Physico-Chemical Biology of Moscow State University
"Newspaper.Ru»
Blocking of cell division in case of DNA damage preceding the degeneration of cells into tumor cells occurs away from the cell nucleus – in the mitochondria, the "power stations" of a living cell. The author of this study, a biochemist from Moscow State University, Alexandra Evstafyeva, told the newspaper.Ru" about how it took place, and about the importance of understanding cellular processes for fundamental and applied science.
Our study, published in the Proceedings of the National Academy of Sciences (Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway), is devoted to the protein p53, which is a suppressor (suppressor) of the development of cancerous tumors.
p53 is a tumor suppressor protein encoded in humans by the TR53 gene. If a mutation occurs in this gene, then a person may become more susceptible to the development of a malignant tumor of the tissue in which this mutation occurred. p53 is extremely important for multicellular organisms. It regulates the cell cycle and can serve as an anti-oncogene, that is, prevent the development of cancer. Because of this, p53 is sometimes called the "guardian of the genome", "guardian angel gene" or "senior caretaker", referring to its function of maintaining stability, preventing genome mutations.
There are several mechanisms of anti-cancer functions of p53. It recognizes damage to chromosomal DNA and can induce a temporary stop of cell division at the so-called control points (check-point) of the cell cycle. p53 is also able to activate the genes of proteins that correct DNA damage (for example, when a cell degenerates into cancer). During the pause, DNA-repairing proteins get the time they need to work. If the DNA restores normal function, the cells begin to divide again, and their cancer degeneration does not occur. If DNA damage cannot be corrected, p53 is able to start the process of apotosis – programmed cell death. Similarly, p53 can respond to other cellular stresses.
Our work arose at the junction of two topics (the study of the p53 protein and the work of mitochondria), which usually do not overlap much. In the laboratory of molecular Biology of the Gene Institute. Belozersky, which is headed by Professor Andrey Vartapetyan, conducted studies of the activity of the tumor suppressor p53 under the action of various stresses. One of the types of cellular stress is disruption of the mitochondrial respiratory chain. Mitochondria are organelles that are the "energy stations" of the cell. From the mitochondria side, the ideology of the work was determined by Boris Chernyak, head of the bioenergetics Department group, a well-known mitochondrial specialist.
What is the mitochondrial respiratory chain? In the process of energy conversion, electrons contained in nutrients are used. Electron transfer proceeds sequentially through a series of complex protein complexes (numbered from 1 to 4) floating in the mitochondrial membrane and forming a "respiratory chain". Moving along this chain, the electrons successively move to lower and lower energy levels and eventually connect with the oxygen of the air we breathe. In this case, the energy given off by electrons is converted into biologically useful forms, in particular, into the energy of adenosine triphosphate (ATP).
An interesting phenomenon was discovered in our work. It turned out that when the electron transfer chain was blocked at the level of complexes 1, 2 or 4, the activity of the tumor suppressor p53 remained at the initial low level. However, when electron transfer through complex 3 of the mitochondrial respiratory chain was disrupted, significant activation of p53 occurred. This means that the malfunctions in the respiratory circuit themselves are not as important for the cell as stopping the flow of electrons through complex 3.
In the latter case, the signal of misfortune is quickly transmitted to the cell nucleus, the level and activity of p53 increases sharply, as a result of which the work of the genes responsible for stopping the cell cycle is activated. The cells stop dividing, and after a while the mechanism of programmed cell death – apoptosis - turns on in them.
Since malfunctions in the respiratory chain occur in the mitochondria, and activated p53 works in another part of the cell, in the nucleus, there must be a way to transmit a signal from the mitochondria to the cell nucleus. We started searching for this signal path. We cannot say that we have found all its links, but the key link has been identified. It turned out that the DHODH enzyme is responsible for signal transmission, which is involved in the biosynthesis of pyrimidine nucleotides (monomeric blocks for the synthesis of new DNA and RNA molecules). This enzyme is located in the mitochondrial membrane near complex 3 of the respiratory chain. Stopping the flow of electrons through complex 3 leads to disruption of this enzyme and, as a consequence, stopping the synthesis of pyrimidine nucleotides.
Synthesis of RNA and DNA occurs in the cell nucleus, and violation of each of these processes can lead to activation of p53. We have shown that the lack of monomeric blocks for the formation of new RNA and DNA molecules in a dividing cell is the reason for the activation of p53. Thus, the addition of pyrimidine nucleotides to the cell growth medium turned off the activation of p53 when complex 3 was inhibited, and the cells survived. So, in our work it was shown for the first time that the biosynthesis of pyrimidine nucleotides is a link between the respiratory chain of mitochondria and the tumor suppressor p53. The identification of a new p53 activation pathway is important both from the point of view of fundamental science and for the development of cancer treatment methods.
Our research team is based at the Institute of Physico-Chemical Biology named after Belozersky (is a division of Moscow State University). In addition, the Institute closely cooperates with the Faculty of Bioengineering and Bioinformatics of Moscow State University, the unofficial name of this symbiosis is "institute-faculty". The staff of the Institute, actively working in various fields at the junction of biology with physics, chemistry or computer science, not only give lectures, conduct seminars and workshops; an essential element of education is the scientific work of students in the laboratories of the Institute, starting with junior courses. The staff of the institute become their "tutors" – this is the name (following the example of elite educational institutions in England) of the student's mentor, who helps him to join the scientific work. Perhaps this is a prototype of the organization of "piece" education, which is best able to prepare students for future work in the field of science.
Students and postgraduates of the faculty took an active part in our work. The first author is Anastasia Khutorenko, a graduate student of the faculty; the second author is Vladimir Rudko, a student. Nastya Khutorenko and Volodya Rudko started working in the Laboratory of Molecular Biology of the gene (Head of the laboratory, Prof. A.B. Vartapetyan), as third-year students. I became their tutor, taught them experimental work and involved them in the study of the mechanisms of activation of the tumor suppressor p53 when inhibiting the respiratory chain of mitochondria. As a result, Nastya defended her thesis with honors and continued to work on this topic in graduate school. Vladimir defended his thesis at the end of May 2010, also with honors.
In addition, we actively collaborated with Peter Chumakov, who is also the head of the laboratory at the Lerner Research Institute (Cleveland, USA) and at the IMB RAS. Being a world-class specialist in the p53 tumor suppressor, he constantly helped us both ideologically (we planned experiments together and discussed their results), and carried out prompt delivery from the USA of vectors, cell lines and antibodies necessary for the work.
Portal "Eternal youth" http://vechnayamolodost.ru30.06.2010