University of Rochester

Team Identifies Switch for Tumor Suppressor Gene

March 5, 1997

Scientists have identified the protein that determines whether or not a tumor suppressor gene is able to do its job of slowing down or stopping cell growth. The work is a first step toward better control over a gene that plays a role in many cases of human cancer.

The research by a team from the University of Rochester Cancer Center is on the retinoblastoma (RB) gene, one of the first known in a class of genes known as tumor suppressors, whose job it is to rein in cell growth. The work, by Associate Professor John Ludlow, graduate student Deidre Nelson, and post-doctoral researcher Nancy Krucher, appears in the Feb. 14 issue of the Journal of Biological Chemistry.

Cancer is a tale of cells growing out of control, and genes that make proteins that speed up or slow down cell growth are often pivotal in the disease. One such gene codes for the RB protein, which suppresses cell growth. The RB protein is present in all healthy cells, but a mutation can lead to cancer. If this mutation occurs in cells destined to form the eye, a rare but deadly form of childhood eye cancer known as retinoblastoma occurs. More commonly, the gene is missing or mutated in many types of cancer cells such as those found in the lung, breast, and ovary.

"In all cancers, you have cells that proliferate uncontrollably," says Ludlow, the lead investigator and co-author of the book, Tumor Suppressors: Involvement in Human Diseases, Viral Protein Interactions, and Growth Regulation. "We all hope that in the future, we'll be able to put the brakes on runaway cancer cells. One way of doing that may be to control a cell's proliferation through manipulation of the RB protein."

The Rochester group has identified the protein that activates RB to slow down cell proliferation. The protein, known as PP1c, does its work during a very narrow time frame during mitosis, when a cell is dividing.

PP1c turns on RB through a chemical process known as de-phosphorylation, a common process in the body where a protein known as a phosphatase strips phosphate groups off a protein. The stripped-down version of the RB protein suppresses growth by knocking out proteins that a cell needs to proliferate. When the RB protein is decorated with phosphate groups, as it is in many cases of human cancer, RB no longer knocks out these proteins, and cells grow out of control.

"To grow correctly, a cell needs both a gas pedal and a brake pedal," says Ludlow. "The RB protein acts like the brake pedal, reining in growth in a precise and controlled manner. Disable that brake pedal and cells can grow out of control."

The team's research is funded by the National Institutes of Health and by the Sally Edelman and Harry Gardner Cancer Research Foundation of Hilton. Several times a year the group pulls together the Hilton community to raise money for cancer research. Since 1985 the group has contributed nearly one quarter of a million dollars for research at the University of Rochester Cancer Center. The group's next fundraiser is its annual steak roast and raffle Saturday, March 8 at the Hilton Exempt Club from 1 to 6 p.m.