Sci. Aging Knowl. Environ., 9 July 2003
Cancer or Aging, Take Your Pick
Protein that keeps aging on pace might help oncogene do its dirty work
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/27/nw97
Key Words: oncogene telomerase RNAi MAX
Can't live without it, can't live with it: A protein whose absence fosters a premature aging syndrome might promote some types of cancer, according to new research. The protein, WRN, ramps up in response to a known cancer-causing protein and helps cells retain their vitality. The study provides a new angle on WRN's function and adds evidence to the idea that cancer-averting mechanisms doom animals to age quickly.
Werner syndrome patients develop untimely cataracts, atherosclerosis, and wrinkled skin (see "Of Hyperaging and Methuselah Genes"). The disease results from a glitch in a gene whose protein product--WRN--apparently helps maintain DNA; cells from Werner syndrome patients harbor damaged chromosomes (see Fry Review). Perhaps in response to such catastrophe, these cells split unusually few times in culture; instead, they enter a state known as senescence, in which they remain alive but cease dividing. Senescence might hasten decrepitude in animals by depleting cells crucial for keeping tissues healthy, but it might benefit organisms by freezing damaged cells that otherwise could turn cancerous (see "More Than a Sum of Our Cells"). A tumor-promoting protein called Myc activates several genes that prevent senescence, so cancer researcher Carla Grandori of the Fred Hutchinson Cancer Research Center in Seattle and colleagues wondered whether the molecule boosts WRN output.
The team observed that the more Myc a cell line bore, the more WRN it harbored. In addition, Myc glommed onto the WRN gene in a test tube and in cells, intimating that Myc controls WRN production.
The group engineered connective tissue cells from Werner syndrome patients to make copious amounts of Myc. These cells grew for a short time but then entered senescence, whereas control cells with normal WRN kept dividing. This result implies that WRN normally protects Myc-manufacturing cells from senescence. Cells from Werner patients accumulate mutations, so the cells' slumber might not stem directly from the loss of WRN. To rule out that possibility, the team engineered normal human connective tissue cells to produce extra Myc and then hindered the production of WRN. Like the Werner syndrome cells, these cells entered senescence; those with bonus Myc and normal WRN continued to reproduce. Previous studies showed that Myc encourages DNA copying but induces the strands to break, so perhaps Myc employs WRN to minimize this damage and keep cells healthy enough to divide, says Grandori.
The paper establishes a novel link between Myc and WRN, says cancer researcher Dean Felsher of Stanford University. "It's the first compelling argument that Myc is wired to prevent genomic instability." He'd like to know whether cells that produce excess Myc accumulate more chromosomal damage if WRN is absent. Grandori notes that Werner syndrome patients don't escape cancer. But they develop tumor types that typically involve alterations in genes other than Myc. Her team is currently investigating whether tying up WRN in Myc-spurred tumors will minimize their growth. Some studies suggest that forestalling cancer speeds aging (see "Having It All After All"); further experiments should reveal whether stemming WRN activity constitutes a similar Faustian bargain.
--R. John Davenport; suggested by Greg Liszt
July 9, 2003
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