Booby Trap: Cancer gene spurs production of DNA-assaulting chemicals that alert and defuse rescue molecule (Cancer; Oxidative damage)
Authors: Aschwanden Christie 
Published: August 2003

Advancing age doesn't just spur ear hair growth and the development of crow's feet, it's also a powerful carcinogen: Cancer risk increases dramatically as people get older. Malignant cells possess severely jumbled DNA, which lays the groundwork for the genetic havoc that allows unbridled cell division. It's "like a bomb went off in the nucleus," says molecular geneticist Ronald DePinho of the Dana-Farber Cancer Institute in Boston. A new study suggests that cancer-spurring genes detonate these bombs at least in part by generating harmful molecules that might hamper the very protein that normally diverts a cell from the dark side.
Researchers have long known that when mutations crank up the expression of cancer-causing genes called oncogenes, the p53 protein restrains cell division. If additional mutations disable p53, as is the case in more than half of all human cancers, tumors can result. How oncogene activation calls p53 to arms is mysterious, but researchers know that p53 responds to DNA damage.

"We wondered whether oncogenes were creating a biochemical change in the cell that ultimately led to DNA damage, and that's why p53 was being activated," says Geoffrey Wahl, a geneticist at the Salk Institute for Biological Studies in La Jolla, California, and the paper's senior author. To find out, his group studied normal human fibroblasts--connective tissue cells--engineered to contain a copy of the
c-myc
oncogene that switches on in response to a drug. Activating
c-myc
yielded rampant DNA damage, particularly the double-stranded breaks so common in cancer cells.

Wahl suspected that
c-myc
might wreck DNA by spurring the formation of toxic reactive oxygen species (ROS) (see
"The Two Faces of Oxygen"
). Using a fluorescent dye that binds the chemicals, the scientists uncovered a two- to threefold increase in the amount of ROS upon
c-myc
activation. Adding the antioxidant
N
-acetyl-
l
-cysteine to cells that produce c-Myc protein significantly decreased ROS concentrations and cut the amount of DNA damage by about 80%. Cells that churn out c-Myc also carry elevated amounts of p53 in its functional form, further experiments revealed.

Together, the results suggest that c-Myc might fire up p53 by creating ROS, which in turn damage DNA. Although these events would normally prompt p53 to halt cell division, c-Myc also appears able to override p53. The oncogene counteracted p53's ability to put the brakes on cell proliferation in response to ionizing radiation. Ten times more c-Myc-producing cells than control cells continued splitting after exposure to gamma rays. Wahl speculates that oncogene-induced ROS could cause additional mutations that diminish p53 function and allow a small percentage of cells to become cancerous.
Other studies have linked ROS to cancer, but this is the first to show that activated oncogenes can generate ROS and contribute to the genomic instability that characterizes cancer cells, says DePinho. The issue of genome instability "stands at the nexus of aging and age-related disorders," he adds. Understanding the phenomenon could uncover ways to reduce the cancer risk that comes with age. That prospect raises hopes for leaving cancer worries behind and making spurious tendrils the worst part of growing old.
--Christie Aschwanden

O. Vafa, M. Wade, S. Kern, M. Beeche, T. K. Pandita, G. M. Hampton, G. M. Wahl, c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: A mechanism for oncogene-induced genetic instability.
Mol. Cell
9
, 1031-1044 (2002).
[Abstract]
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