Researchers at Umeå University can now show that cells that grow forever get this capacity through gradual changes in the expression of genes that govern the repair of DNA damage and regulate growth and cell death. The research also shows that activation of the enzyme complex telomerase, which is necessary for unlimited growth, occurs late in this process.
The study, published in the April issue of the journal Aging Cell, was performed by a research team directed by Professor Göran Roos at the Department of Medical Bioscience, Pathology. It is about how cells' telomers (=repetitive DNA sequences on the ends of chromosomes) are regulated during the process that leads to eternal life of cells.
One type of blood cells, lymphocytes, were analyzed on repeated occasions during their cultivation in an incubator until they achieved the ability to grow an unlimited number of cell divisions, a process that is termed immortalization. In experiments, immortalization can be achieved following genetic manipulation of cells in various ways, but in the lymphocytes under study this occurred spontaneously. This is an unusual phenomenon that can be likened to the development of leukemia in humans, for example.
The ends of chromosomes, the telomers, are important for the genetic stability of our cells. In normal cells telomers are shortened with every cell division, and at a certain short telomer length they stop dividing. With the occurrence of genetic mutations the cells can continue to grow even though their telomers continue to be shortened. At a crticially short telomer length, however, a so-called crisis occurs, with imbalance in the genes and massive cell death. In rare cases the cells survive this crisis and become immortalized. In previous studies this transition from crisis to eternal life has been associated with the activation of telomerase, an enzyme complex that can lengthen cells' telomers and help stabilize the genes. A typical finding is also that cancer cells have active telomerase.
The current study shows that cells initially lose telomer length with each cell division, as expected, and after a while enter a crisis stage with massive cell death. Those cells that survive the crisis and become immortalized evince no activation of telomerase; instead, this happens later in the process. The Umeå researchers found that the expression of genes that inhibit telomerase is reduced in cells that get through the crisis, but telomerase was not activated until positively regulating factors were activated, thus allowing the telomers to become stabilized through lengthening. By analyzing the genetic expressions the scientists were able to show that the cells that survived the crisis stage had mutations in genes that are key to the repair of DNA damage and the regulation of growth and cell death. This discovery provides new insights into the series of events that needs to occur for cells to become immortalized, and it will have an impact on future studies of leukemia, for example.
The studies were carried out in collaboration with the Centre for Oncology and Applied Pharmacology, University of Glasgow and the Maria Skodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw.
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