couple of citation superstars are at it again, with a paper that built a bridge between two well studied, but hitherto unlinked, genes and demonstrated the first connection between the loss of a tumor suppressor gene and the activation of an oncogene. 

In paper #9, Bert Vogelstein and Kenneth Kinzler of the Johns Hopkins Oncology Center, Baltimore, Maryland, and their colleagues show that the most common gene for colon cancer works by suppressing c-MYC, which had been linked to a variety of cancers more than 20 years ago, but with no clue as to how it caused cancer.

   More than 85 percent of colorectal cancers have a mutation that truncates the adenomatous polyposis coli (APC) gene. When it is functioning normally APC protein suppresses tumorous growth. It binds to and promotes the degradation of b-catenin, which in turn binds to members of the T-cell factor 4 (Tcf-4) family of transcription factors. Tcf-4 activates certain genes. So a mutated APC gene allows more b-catenin to bind to Tcf-4, stimulating cancerous growth, perhaps as a result of Tcf-4 activating an oncogene–but which gene?

   Kinzler and his team developed a technique called serial analysis of gene expression (SAGE), which they use to track active genes. SAGE depends on creating short DNA copies, or tags, of active mRNA in the target cells. Using cells with and without a functional APC gene resulted in a huge collection of tags, most of which were present at the same level in both sets of cells. But a few differed, either over-expressed or repressed in cells with the APC gene. Because they knew APC suppresses b-catenin the team focused on the repressed tags; to their surprise one of the most highly down-regulated tags corresponded to c-MYC, one of the first oncogenes to be identified.

   To confirm the possibility that APC directly controls c-MYC via b-catenin, the team stitched a c-MYC promoter sequence to a luciferase reporter gene. Any cell containing this construct–and luciferin–would glow gently when the c-MYC gene was active. Inserted into colorectal cancer cells, on went the light, only to be turned off by the addition of APC protein. And b-catenin also activated the reporter construct.

   "This ends one chapter of the APC story," as Vogelstein said at the time of the paper's publication, but begins many more. "Master genes such as...APC usually don't work on just one pathway. So c-MYC is probably not the only gene whose expression is controlled by APC. We are working to find the others."

   The model that emerges is that in normal colon cells APC prevents b-catenin from binding to Tcf-4 and activating c-MYC. The vast majority of colorectal tumors have an inactive APC gene, though a few–about 10 percent–have normal APC but a mutated b-catenin gene; either way, c-MYC is switched on, which transforms the cell and leads to tumorous growth. What is particularly neat about this work is that it makes sense of a puzzling observation: Although c-MYC has long been known to be active in colorectal tumors, mutations of c-MYC are very rare in colon cancer. In other cancers, c-MYC itself is mutated. If APC controls c-MYC, that solves the problem.

   It also suggests therapeutic possibilities: the discovery that c-MYC is a final link in the chain that causes colorectal cancer, the number two cause of cancer deaths in the United States, "brings up an obvious and potentially powerful way to disrupt that interaction," according to Vogelstein, whose lab has been actively searching for ways of blocking the activation of c-MYC.