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December 28, 2005


--"PatA" is believed to be the first molecule found to do so in human cells

A natural chemical made by a New Zealand sea sponge exerts its deadly effects on cancer cells by preventing the cells' protein-building machinery from turning on, Johns Hopkins scientists report in the Dec. 9 issue of Molecular Cell.

The chemical's anti-cancer effects have been known since 1991, but this is the first comprehensive report to show how the molecule, known as pateamine A (PatA), stalls the growth of so-called eukaryotic cells -- cells that have membranes and a nucleus.

"Agents that interfere with protein production in bacteria are already useful antibiotics, but this is the first small molecule found to interfere specifically with the earliest steps of protein production in human cells," says the study's leader, Jun Liu, Ph.D., a professor of pharmacology and molecular sciences in the Johns Hopkins Institute for Basic Biomedical Sciences.

Although any clinical applications of PatA or related molecules are likely many years away, Liu notes, PatA's abilities offers investigators the chance to probe the earliest steps in protein production and the biology of so-called "suicide" in human cells.

"The whole idea of chemical biology is that we can use active molecules like PatA as bait to fish out their biological targets, which sheds light on normal biology and can clarify why the molecules' interaction is important," says Liu, whose research has focused on using chemical biology to study the regulation of the immune system. "This is incredibly powerful as scientists begin creating networks, not just linear pathways, of biological understanding."

But to use chemical biology to probe a particular aspect of biology, scientists have to have a small molecule that interferes with it.

"Many molecules are known that interfere with reading, or transcribing, genes' DNA to get RNA," says Liu. "But no one had found a molecule that specifically prevents initiation of the next step, the reading, or translation, of the RNA to build a protein."

In cells from yeast to humans, translating RNA to build a protein is accomplished by complicated machinery called the ribosome, made up of a number of different parts that come and go in order to activate the machinery, turn it off, or move it to the next step.

The very first thing the ribosome must do is identify and latch onto the right spot on the right RNA, a step called initiation. A protein called eIF4A normally jump-starts this process by helping to recruit specific partner proteins to the ribosome.

"Initiation may sound simple, but in the cell, hundreds if not thousands of RNAs are floating around and the ribosome has to find and bind to the right one at the right site," says Liu. "It's like having a bucket of snakes and having to pick up a particular snake by the head."

In their experiments, the researchers found that PatA binds to eIF4A and actually increases the protein's enzymatic activity. Delving further, however, the researchers discovered that initiation of protein building is blocked because, once bound to PatA, eIF4A cannot interact properly with its normal partner proteins, eIF4G and eIF4B.

"Under normal circumstances, eIF4A forms a stable complex with eIF4G and interacts only transiently with eIF4B, but PatA changes all that," says Liu. "Binding to PatA causes eIF4A and eIF4B to form a stable complex, which is packaged into so-called stress granules -- clumps of ribosomes and RNAs the cell puts together to temporarily halt protein production in a crisis."

Liu's laboratory is now studying how the clumps are involved in cellular suicide, a process called apoptosis. They will eventually be testing a version of PatA, made by their long-term collaborator Daniel Romo, a synthetic chemist at Texas A & M University, that's easier to synthesize and more stable than the natural product. Eventually, the researchers will test whether their versions of PatA might be drug candidates.

The researchers were funded by the National Cancer Institute, the Keck Center, the National Institute of General Medical Sciences, and the Canadian Institute of Health Research.

Authors on the paper are Woon-Kai Low, Yongjun Dang, Tilman Schneider-Poetsch, Zonggao Shi and Jun Liu of Johns Hopkins; Nam Song Choi and Daniel Romo of Texas A & M University, and William Merrick of Case Western Reserve University.

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