A New Interpretation of the Cancer Genes of Chinese Scholars

Release date: 2013-01-17

The tumor suppressor gene p53 is the single most frequently mutated gene in human tumors, and its importance has become a consensus in the research field. P53 can prevent cell carcinogenesis by promoting cell aging. Normally, a mutant or dangerous cell will receive a signal to stop growth or death, but cells lacking p53 will ignore these signals. Clearly, the p53 pathway is a very attractive target for drug developers. But at present, the strategy of marking the p53 pathway is often difficult to achieve. This is because the vast majority of p53 regulatory proteins perform functions through protein interactions, and such mechanisms of action make them difficult to become ideal drug targets. In contrast, enzymes can often be a good target for drug action. Now researchers at the Perelman School of Medicine at the University of Pennsylvania have discovered a new class of p53 target genes and regulatory molecules that are expected to be good drug targets. Xiaolu Yang, a professor of cancer biology at the University of Pennsylvania, and his team found that p53 and malic enzyme are in a molecular feedback loop, suggesting that p53 activity is also involved in metabolic regulation. The study was published in advance on the Nature magazine website. Prior to this, Professor Yang's laboratory had discovered the role of p53 in glucose metabolism. Professor Yang pointed out that this new discovery explains the cause of cellular aging caused by metabolic stress, and p53 is the molecular sensor of metabolic stress. “We have discovered an important regulatory mechanism and effector mechanism for p53,” Professor Yang said. It is noteworthy that this study not only makes malic enzymes a new potential target for cancer treatment, but also suggests that malic enzyme may be a regulator of normal cell aging, but these two possibilities remain to be seen. Further research confirmed. When cells are damaged and may become cancerous, p53 ages these cells from developing into tumors. Metabolic factors also regulate cell aging, but people have not understood the molecular link between the two processes. Professor Yang and his team studied malic enzyme 1 and malic enzyme 2 (ME1 and ME2). Malic enzyme is responsible for catalyzing the production of pyruvic acid, the end product of glycolysis, an intermediate product, and stores energy in the process. Malic enzymes are important for regulating metabolism to accommodate cell proliferation, which are coordinated with cellular energy and proliferative status. The researchers found that p53 inhibits the expression of malic enzyme, while the loss of p53 increases the abundance of malic enzyme. In contrast, malic enzyme also regulates p53, and the absence of malic enzyme enhances p53 activation and induces cell aging by down-regulating the p53 inhibitor (Mdm2) or generating oxygen free radicals. Professor Yang explained that this forms a “feed-forward loop” that activates p53 to inhibit malic enzyme expression, while decreased levels of malic enzyme and further up-regulation of p53 lead to cell aging. On the other hand, up-regulation of malic enzyme inhibits p53, allowing it to relax the inhibition of malic enzyme expression, thereby increasing the level of malic enzyme. "This is a loop," he said. “Along this cycle, there is considerable activation.” The study also yielded the same results in animal models. Studies have shown that even in the absence of p53 in tumor cells, a lack of ME1 or ME2 reduces tumor weight, indicating that this additional function of malic enzyme is independent of p53. In addition, overexpression of malic enzymes leads to an increase in tumors. Professor Yang believes that malic enzyme is a molecule that links cell aging and metabolism. Not only are these enzymes expected to be targets for anticancer drugs, but equally important they also play a role in the normal aging of cells. "Aging is aging at the cellular level and is a good starting point for us to understand the mechanism of aging," Professor Yang said. He also pointed out that this study demonstrates the link between caloric restriction and longevity.

Source: Nature