Researchers zero in on few proteins as cancer drug target

Researchers with University of California, Berkeley, have found a promising new drug target within the pathway that controls the production of a cancer cell's thousands of proteins and it appears to control production of only a few percent of the proteins critical to regulating the growth and proliferation of cells.

The target, according to a study published online Wednesday and in the Aug. 4 print issue of the British journal Nature, is a protein that binds to messenger RNA, or mRNA, and helps get it started along the production line that ends in a fully assembled protein. A drug blocking this binding protein could shut off translation of only the growth-promoting proteins and not other life-critical proteins inside the cell.

As mRNA holds the cell's blueprint for making protein, "if cancer cells are making too much mRNA, you could shut them down by preventing them from using that mRNA to make protein," said Jamie Cate, a UC Berkeley professor of molecular and cell biology and of chemistry and leader of the study. "Because this binding protein is not used for general protein production - not every mRNA uses this - you may be able to get a more specific anti-cancer effect by targeting that alone."

To researchers' surprise, the protein is part of a larger assembly of proteins called eukaryotic initiation factor 3, or eIF3, that has been known and studied for decades. "No one suspected its undercover role in the cell," said first author Amy Lee, a former UC Berkeley American Cancer Society postdoctoral fellow and now an assistant professor at Brandeis University. "This may be because eIF3's ability to selectively control mRNA translation is turned on only when it binds to the set of specialized mRNAs."

Cancer is characterized by uncontrolled cell growth, with the protein production machinery goes into overdrive to provide the building materials and control systems for new cells. Hence, biologists have studied the proteins that control how genes are transcribed into mRNA and how the mRNA is read and translated into a functioning protein. It was found more than 40 years ago that a so-called initiation protein must bind to a chemical handle on the end of each mRNA to start it through the protein manufacturing plant, the ribosome. Until now, this initiation protein was thought to be eukaryotic initiation factor 4E, or eIF4E.

Earlier this year, Cate and Lee discovered that for a certain specialized subset of mRNAs - most of which have been linked somehow to cancer - initiation is triggered by a different protein in eIF3. Before, that protein was thought to be just one of a dozen or so general initiation factors required for mRNA translation. Instead, they discovered that eIF3, an assembly of 13 separate proteins, binds to unique three-dimensional structures found only in this special subset of mRNAs.

"What we found is that another protein, hiding in plain sight for over four decades, can also bind the chemical handle on the end of mRNAs to promote translation," Cate said. "It's a component of eIF3 - a protein called eIF3d - which has never before been connected to binding the handle." Subsequent X-ray crystallography of eIF3d revealed the structural rearrangements that must occur when eIF3 binds to the mRNA three-dimensional structures and which open up the secret compartment.

Binding between eIF3 and these mRNAs opens up a pocket in eIF3 that then latches onto the end-cap of mRNA to trigger the protein production, or "translation," process. "To me, it's like finding a secret lever that opens a hidden drawer in an old-time desk," Cate said. "The desk has been around over one and half billion years and many have studied it for decades, but we figured out how to trigger the opening."
The research hints that this secret lever, which triggers translation of only a special subset of mRNAs - perhaps only 500 out of some 10,000 mRNAs produced by a cell - will be found to play a critical role in other diseases besides cancer, as well as in plants and animals.