St. Louis, Sept. 29, 2000 — Researchers have identified two proteins that help immune cells commit suicide. Defects in one of these proteins have been linked to lymphomas.

The findings are published in the Oct. 5 issue of Nature. Natalie A. Lissy, a graduate student in pathology at Washington University School of Medicine in St. Louis, is first author. Steven F. Dowdy, Ph.D., an assistant professor of pathology and Howard Hughes Medical Institute assistant investigator, directed the study.

Many cells are programmed to kill themselves after they complete their biological duties or become damaged. Those that fail to obey this command accumulate in the body. Because every cell has the potential to mutate into a cancerous cell, excess cells increase the probability of mutations. Mutations in immune cells called T cells are particularly dangerous instigators of cancer.

Previous studies show that a protein called p53 regulates cell death that is induced by DNA damage. By acting in this way, p53 suppresses tumor growth. "P53 proteins are the guardians of the genome," Dowdy explains. "They make sure there is no DNA damage in each cell. If there is, they command the cell to commit suicide."

Scientists believe that half of all cancers arise because the p53 gene becomes mutated. The resulting protein therefore fails to do its job, and fewer cells complete the suicide mission.

Dowdy and colleagues have determined that two other proteins play important roles in programmed cell death. They are p73, a relative of p53, and a protein called E2F1. Previous research has implicated both proteins, but the Washington University paper presents the first empirical evidence that the two are essential for the programmed death of T cells.

It was known that p73, though related to p53, fails to kill cells that contain damaged DNA. Researchers therefore set out to identify the independent pathway that enables p73 to regulate programmed T-cell death.

To inhibit E2F1 or p73, the team used a relatively new technique called TAT-mediated protein transduction, which Dowdy’s laboratory developed. It blocks the actions of specific proteins in almost 100 percent of cells under study and allows the cells to develop normally. In comparison, standard methods bombard cells with artificially high levels of protein blockers that get into about one-fifth of the cells.

Inactivating either E2F1 or p73 with the new technique stopped the programmed cell death of human and mouse T cells, even though p53 levels remained the same. The researchers therefore concluded that both E2F1 and p73 proteins are involved in regulating programmed cell death.

"There are still some basic-science questions to ask, but the general biology is in place," says Dowdy. "When a particular receptor is stimulated, it activates E2F1, which turns on the p73 protein. Then p73 activates the machinery that causes that cell to die."

Dowdy and colleagues plan to determine how this pathway operates. They believe the existence of a cell-death mechanism that does not involve p53 has important implications for cancer research and for understanding autoimmune diseases that result from abnormal T-cell death.

Lissy NA, Davis PK, Irwin M, Kaelin WG, Dowdy SF. A Common E2F1 and P73 Pathway Mediates Cell Death Induced By TCR Activation. Nature, Oct. 5, 2000. This work is supported by the Howard Hughes Medical Institute.