Cells have a finite number of divisions, and at each division, chromosome ends, or telomeres, shorten. When the telomeres diminish to a certain length, a number of complex pathways are triggered that halt cell division. In cancer, though, this signaling pathway is disrupted, resulting in unrestrained cell growth. Understanding the triggering mechanisms and pathways involved may lead to better cancer drug development. Researchers at Brown University, Providence, R.I., further described the metabolic pathway involved in cell senescence. Their paper, "Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21, but Not p16," was published with a related editorial in Molecular Cell. [Herbig et al., vol. 14, pp. 501-513 (2004)]

John Sedivy, PhD, and his team at the Brown University Department of Molecular Biology, Cell Biology and Biochemistry, worked on single human cells. This was a different approach, one that allowed a more focused look at the processes involved. Says Sedivy, "Typical cultures are mosaics. Some cells are doing one thing; some cells are doing different things; some cells are doing both things. You could never unravel this if we hadn't looked at the single cell paths. We did show, quite clearly and convincingly, that there are telomere-independent pathways operating in these cells."

Lead author Utz Herbig, PhD, says, "We asked, if there's a DNA damage response, which pathway is it taking? What is the downstream affecter that causes the cell cycle arrest you see in old cells, in senescent cells? We found, through co-localization studies using antibodies against proteins that are known to be involved in the specific pathway, that the damage at the telomeres causes activation of the tumor suppressor p53, which then results in up-regulation of the cell cycle inhibitor p21. This protein is primarily responsible for causing the senescent arrest during telomere shorting."

They found further involvement of yet another protein, the cell cycle inhibitor p16, or kinase inhibitor, that is up-regulated in senescence. They were unable, however, to link it to the telomere pathway. Says Herbig, "This other protein is up-regulated by other mechanisms we don't understand yet. It's probably a response to extrinsic signals. Not intrinsic signals like the telomeres, but some other factors that have been up-regulated in response to high oxygen conditions. We're trying to figure out how p16 is regulated, but we know it's not controlled by the telomere pathway."

Regulation of the p16 pathway is going to be the primary continuing focus of Sedivy and Herbig's research, building on what they learned from this study. Says Herbig, "It provides a groundwork, a basic understanding of how cells become senescent, and this is very important for understanding tumorigenesis."

"Once you know the nuts and bolts," says Sedivy, "the protein components of the pathway, these become obvious drug routes. Some of these already are drug targets. We didn't discover any new players." Some of these proteins have been intensively studied in the DNA repair field, says Sedivy, and knowing that they also participate in the senescence process is going to be very useful.

By Mark Terry