New Clues into How Cells Achieve Immortality

Swedish investigators can now show that cells that grow forever, becoming immortal, obtain this capacity through gradual changes in the expression of genes that control the repair of DNA damage and regulate growth and cell death. Their research also shows that activation of the enzyme complex telomerase, which is essential for unlimited growth, occurs late in this process.

The study's findings, published in the April 2010 issue of the journal Aging Cell, was performed by a research team from Umeå University (Sweden) and directed by Prof. Göran Roos at the department of medical bioscience, pathology. The study's findings provide more insights into how cells' telomeres are regulated during the process that leads to perpetuating the 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 atypical phenomenon that can be compared to the development of leukemia in humans, for example.

The ends of chromosomes, the telomeres, are important for the genetic stability of organisms' cells. In normal cells, telomeres are shortened with every cell division, and at a specific short telomere length, they stop dividing. With the occurrence of genetic mutations, the cells can continue to grow even though their telomeres continue to be shortened. At a critically short telomere 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 earlier research, this transition from crisis to eternal life has been associated with the activation of telomerase, an enzyme complex that can lengthen cells' telomeres and help stabilize the genes. A typical finding is that cancer cells have active telomerase.

The current study demonstrated that cells initially lose telomere 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 discovered that the expression of genes inhibiting telomerase is reduced in cells that get through the crisis, but telomerase was not activated until positively regulating factors were activated, thus allowing the telomeres 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 crucial 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 performed in collaboration with the Center for Oncology and Applied Pharmacology, University of Glasgow (UK) and the Maria Skodowska-Curie Memorial Cancer Center and Institute of Oncology (Warsaw, Poland).

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