Keeping the Bad Guy Down: New potential tumor-suppressor gene

Abstract

In the good guy-bad guy world of cancer, shifty proteins often run afoul of cellular law, prompting molecular sheriffs to action. One cellular citizen--the protein Akt--normally lives a quiet life, performing its civic duty in the insulin-like growth factor-1 (IGF-1) and insulin mammalian signaling pathways. These pathways manage cell growth in mammals, and related ones regulate aging in organisms that include worms, flies, and possibly mice (see "Growing Old Together" ). To do its job, Akt slips on a phosphate group. If the protein dons this black hat for too long, however, it triggers a molecular stampede in the IGF-1 signaling pathway, which promotes a half-dozen cancers. Mutations in Akt or its handlers can turn Akt to a permanent life of crime. A corrupt form of the protein, found in many cancers, never removes its phosphate; this version transforms innocuous cell lines into deadly tumor inducers in mice. In healthy cells, a white-hatted cellular cowboy--a tumor-suppressor gene known as PTEN --keeps Akt in check. Research has now uncovered a second marshal in the mammalian struggle against unrestrained Akt that keeps the phosphate hat away from the potential scoundrel, preventing it from suiting up in its gunslinger garb. To seek regulators of Akt, Hemmings and colleagues used a technique to fish out molecules that bind to a bait protein--in this case, a piece of Akt--from a pool of human proteins. Using a variety of biochemical techniques, they showed that one protein--which they named CTMP--prevents Akt from acquiring the phosphate group that leads to its hyperactivity. They then produced CTMP in a cell line made cancerous by the delinquent Akt. CTMP quashed the ability of these cells to grow uncontrolled in culture dishes and reduced the speed at which they induce tumors in mice. These results suggest a rationale for new cancer therapies: Perhaps a drug that mimics CTMP could wrangle in a lawless Akt. The researchers also found that the amount of CTMP in cells mirrored that of PTEN and propose that the two might be regulated in parallel. If so, CTMP could be partly responsible for Akt lawlessness that is now blamed on a slacking PTEN. CTMP provides a new focus for labs that are trying to discover how IGF-1-like signaling pathways control life-span. Perhaps this molecular desperado plays a role not just in cancer but also in longevity: It might help decide whether to send cells--or organisms--riding off into the sunset. --Mary Beckman S.-M. Maira, I. Galetic, D. P. Brazil, S. Kaech, E. Ingley, M. Thelen, B. A. Hemmings, Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 294 , 374-380 (2001). [Abstract] [Full Text]