When targeting cancer genes, home in on the 1 percent

July 27, 2016

Most cancer drugs are designed to halt cell growth, the hallmark of cancer, and one popular target is the pathway that controls the production of a cell's thousands of proteins.

University of California, Berkeley researchers have now found a promising new drug target within that pathway that is appealing, in part, because it appears to control production of only a few percent of the body's many proteins, those critical to regulating the growth and proliferation of cells.

The target is a protein that binds to messenger RNA - the cell's blueprint for making protein - 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.

"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 translation - not every mRNA uses this - you may be able to get a more specific anti-cancer effect by targeting that alone."

The finding was a surprise because the protein is part of a larger assembly of proteins called eIF3 -eukaryotic initiation factor 3 - that has been known and studied for nearly 50 years, and no one suspected it's undercover role in the cell, Cate said. 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. Binding between eIF3 and these mRNAs opens up a pocket in eIF3 that then latches onto the end-cap of mRNA to trigger the 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."

Lee and Cate's 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.

"It will be exciting to look in other organisms, such as crop plants and pathogenic fungi, to find out what mRNAs this protein regulates," said first author Amy Lee, a former UC Berkeley American Cancer Society postdoctoral fellow who is now an assistant professor at Brandeis University. "Down the road, one could imagine finding ways of manipulating how mRNAs bind to eIF3 in all of these different systems."

The new findings by Cate, Lee and their UC Berkeley colleagues will be posted online July 27 in advance of publication in the British journal Nature.

Hiding in plain sight

Cancer is characterized by uncontrolled cell growth, which means the protein production machinery goes into overdrive to provide the building materials and control systems for new cells. Hence, biologists for decades have studied the proteins that control how genes are transcribed into mRNA and how the mRNA is read and translated into a functioning protein.

One key insight more than 40 years ago was 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 eIF4E (eukaryotic initiation factor 4E) for all mRNAs.

"When cells don't control how the handle is used, cells can get out of control and cause cancer," Cate said. "Up until now, this has been thought to be due to eIF4E that binds to the handle."

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 a unique tag found only on 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," he 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 tag and which open up the secret compartment. The researchers plan further studies using cryoelectron microscopy to locate the actual trigger that opens the compartment.

"Basically, we found the button that opens the secret door, but we don't really know what the button looks like yet," Cate said.
-end-
In addition to Cate and Lee, the coauthors of the paper are Jennifer Doudna, a UC Berkeley professor of molecular and cell biology and of chemistry, and Doudna's former postdoc Philip Kranzusch, now a member of the faculty Harvard Medical School and the Dana-Farber Cancer Institute. The work was funded by the National Institute of General Medical Sciences through UC Berkeley's Center for RNA Systems Biology. Cate and Doudna are faculty scientists at Lawrence Berkeley National Laboratory.

University of California - Berkeley

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.