29 October 2009

Protein p16 is the second line of defense against cancer

A group of scientists from the University of Rochester (New York), led by molecular biologist Vera Gorbunova, shed light on the mechanism of unusual resistance to the development of malignant diseases of the naked digger (Heterocephalus glaber), a burrowing rodent that lives in deserts.

According to the results of the study published on October 26 in the on-line version of the Proceedings of the National Academy of Sciences in the article "Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat", these unique animals have a molecular mechanism that stops cell division before their density exceeds normal, which usually occurs in tumors.

Naked diggers live longer than all other rodents – their age can exceed 30 years – however, even the most "adult" individuals do not spontaneously develop malignant tumors. Even in the laboratory, it is extremely difficult to create tumor lines from the cells of these rodents. For many years, this mystery, the solution of which can significantly advance the study of the problems of aging and cancer, remained unsolved. Apparently, the Rochester researchers have finally managed to find the long-awaited answer.

The authors cultured the cells of a naked digger to compare their properties with the properties of mouse cells often used in experiments modeling human malignant tumors. However, in the course of their work, they encountered a problem: the cells of the naked digger did not grow when cultivated according to the rules of growing mouse cells.

With a decrease in the number of cells sown per unit surface of the culture plate, the fibroblasts of the skin and lungs of the naked digger proliferated at a normal rate, but the maximum cell density achieved in this case was three times lower than in similar cultures of mouse cells.

This observation led scientists to the idea of increased sensitivity of naked digger cells to cell density and the possible role of this mechanism in preventing the formation of malignant tumors.

The phenomenon of contact inhibition is based on intercellular interaction, which stops cell division at the moment when they completely cover the culture surface with a dense layer one cell thick. This stopping of the cell cycle is regulated by a molecular mechanism based on the accumulation of the protein p27 – cyclin-dependent kinase inhibitor. An increase in the area of intercellular contacts stimulates the synthesis of p27, an increase in the concentration of which inhibits cell division. Another kinase inhibitor, protein p16, is involved in this mechanism, but its role in blocking cell division has so far been considered insignificant.

A significant increase in the level of p16 immediately before stopping the proliferation of cells of the naked digger indicates that in these animals cell division blocks this protein. Moreover, this happens much earlier than p27 stops the proliferation of mouse cells. The authors called this phenomenon "early contact inhibition".

The images show fibroblasts of the skin of a naked digger under conditions of early contact braking (above) and mouse fibroblasts under conditions of normal contact braking (below).

Another proof of the role of p16 in the regulation of cell division of the naked digger was obtained by studying the stem cell line of this animal, which, as a result of spontaneous mutation, lost the ability to early contact inhibition. High levels of p16 were not recorded in this cell line, while the cells behaved similarly to mice, demonstrating an increase in the concentration of p27 during the period of "normal" contact inhibition and stopping division at a density corresponding to the density of mouse cultures. This indicates the presence of two systems of regulation of cell growth in the naked digger, both early and normal contact inhibition. Additional protection against excessive division can be explained by the absence of cancerous tumors in these rodents throughout their long life.

According to Vera Gorbunova, naked diggers may have other systems of protection against malignant diseases that are absent in humans. She adds that mouse models are very informative when studying the effectiveness of cancer treatments, but if we want to understand how to prevent the formation of tumors, it is better to turn to organisms that are more resistant to cancer than mice.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of The Scientist: Secrets of a cancer-free rodent.


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