A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally thought. The key to immortalization is an enzyme called telomerase, which keeps chromosomes healthy in cells that divide frequently. The enzyme lengthens the caps, or telomeres, on the ends of chromosomes, which wear off during each cell division.
…Hockemeyer and his UC Berkeley colleagues, in collaboration with dermatopathologistBoris Bastian and his colleagues at UCSF, found that immortalization is a two-step process, driven initially by a mutation that turns telomerase on, but at a very low level. That mutation is in a promoter, a region upstream of the telomerase gene – referred to as TERT – that regulates how much telomerase is produced. Four years ago, researchers reported that some 70 percent of malignant melanomas have this identical mutation in the TERT promoter. The TERT promoter mutation does not generate enough telomerase to immortalize the pre-cancerous cells, but does delay normal cellular aging, Hockemeyer said, allowing more time for additional changes that turns telomerase up. He suspects that the telomerase levels are sufficient to lengthen the shortest telomeres, but not keep them all long and healthy. If cells fail to turn up telomerase, they also fail to immortalize, and eventually die from short telomeres because chromosomes stick together and then shatter when the cell divides. Cells with the TERT promoter mutation are more likely to up-regulate telomerase, which allows them to continue to grow despite very short telomeres. Yet, Hockemeyer says, telomerase levels are marginal, resulting is some unprotected chromosome ends in the surviving mutant cells, which could cause mutations and further fuel tumor formation. "Before our paper, people could have assumed that the acquisition of just this one mutation in the TERT promoter was sufficient to immortalize a cell; that any time when that happens, the telomere shortening is taken out of the equation," Hockemeyer said. "We are showing that the TERT promoter mutation is not immediately sufficient to stop telomeres from shortening." It is still unclear, however, what causes the eventual up-regulation of telomerase that immortalizes the cell. Hockemeyer says that it's unlikely to be another mutation, but rather an epigenetic change that affects expression of the telomerase gene, or a change in the expression of a transcription factor or other regulatory proteins that binds to the promoter upstream of the telomerase gene.