Neuronal regulators offer potential targets for cancer

Being too brainy can be a bad thing in a junior high cafeteria, where the social hierarchy favors other traits. "Braininess" also causes problems for cells. When a breast cell begins making the proteins normally produced in neurons, for example, it can acquire cancerous properties.

Now, researchers in Stephen Elledge's laboratory at Harvard Medical School (HMS) have identified some of the switches that control this transformation, providing promising new therapeutic targets in some types of cancer. Their results appear in the March 20 issue of Nature.

"These switches play an important physiologic role in neural development and pathologic role in cancer," says first author Thomas Westbrook, who is now an assistant professor at Baylor College of Medicine. "I'm optimistic that we can use small molecules to control them."

In a previous study, Westbrook showed that a protein called REST--which keeps neural programs silent in most parts of the body--serves as a tumor suppressor.

"He's now identified a protein that promotes tumor growth by tagging REST for destruction, thereby activating neural programs," says Elledge, who holds primary appointments in the HMS Department of Genetics and at Brigham and Women's Hospital.

If the protein REST worked at a club, he would be a bouncer, preventing dozens of rowdy patrons from causing trouble. REST serves as a "master repressor," keeping numerous neural genes silent in breast cells, lung cells, etc, where they could wreak havoc. When REST disappears, these genes roar to life, pushing cells to become more like neuron precursor cells.

But cells outside the nervous system keep neural genes silent for a reason. When neural genes get switched on in breast cells anchored to surfaces, for example, they acquire the ability to live without the anchoring that is essential for normal cells to survive. That is, they can grow in suspension, which is a classical characteristic of cancer cells.

After uncovering this role, Westbrook used a technique called RNA interference (RNAi) to search for proteins that reduce REST levels. He reasoned that these proteins might promote tumor formation if expressed outside the nervous system.

The RNAi screen netted a known tumor promoter called β-TRCP. Further genetic tests revealed that β-TRCP binds directly to REST, tagging it for destruction. But REST must be primed with a particular molecule called phosphate for this interaction to occur.

"If we can prevent β-TRCP from binding to REST, we may be able to treat certain tumors that display neuronal gene expression profiles," says Elledge, who is also a member of the HMS-Partners HealthCare Center for Genetics and Genomics and investigator with the Howard Hughes Medical Institute. "Such profiles are remarkably common in epithelial cancers, such as breast cancer and ovarian cancer."

"This discovery is particularly exciting because the scientific community knows how to target enzymes that add and remove phosphate groups from proteins with small molecules," says Westbrook. "Big pharmaceutical companies have devoted lots of resources to accomplishing this task."

Information about the interaction between β-TRCP and REST might also aid researchers in the embryonic stem cell field.

"It's hard to control the differentiation of embryonic stem cells into specialized cells such as neurons," says Westbrook. "If one could prevent β-TRCP from tagging REST for destruction, one could potentially keep embryonic stem cells from turning into neurons. Alternatively, one might be able to make neurons more efficiently by quickening REST destruction."

Source: Harvard Medical School

Related stories:

Probing Question: Fishhooks of addiction
When the American writer Theodore Roethke taught at Penn State from 1936 to 1943, he was known for three things: being a good poet, coaching the men’s tennis team, and falling down drunk, perhaps the latter more than the former. Roethke, a brilliant and tortured man, knew well the seduction of drink and the agony of addiction. In his poem “Journey Into the Interior,” Roethke writes, “In the long journey out of the self, / There are many detours, washed-out interrupted raw places / Where the shale slides dangerously / And the back wheels hang almost over the edge / At the sudden veering, the moment of turning.”
Nerve cells derived from stem cells and transplanted into mice may lead to improved brain treatments
Scientists at the Burnham Institute for Medical Research have, for the first time, genetically programmed embryonic stem (ES) cells to become nerve cells when transplanted into the brain, according to a study published today in The Journal of Neuroscience. The research, an important step toward developing new treatments for stroke, Alzheimer's, Parkinson's and other neurological conditions showed that mice afflicted by stroke showed tangible therapeutic improvement following transplantation of these cells. None of the mice formed tumors, which had been a major setback in prior attempts at stem cell transplantation.
MIT unlocks mystery behind brain imaging
Star-shaped brain cells shown to play key role
In work that solves a long-standing mystery in neuroscience, researchers at MIT's Picower Institute for Learning and Memory have shown for the first time that star-shaped brain cells called astrocytes—previously considered bit players by most neuroscientists—make noninvasive brain scans possible.
Brain stem cells can be awakened, say scientists
Scientists at Schepens Eye Research Institute have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. Their findings are published online this week in the Proceedings of the National Academy of Science (PNAS).
Flow of potassium ions in brain cells is key to sexual arousal
When it comes to sex, a female rat knows how to avoid a communication breakdown. To announce her sexual readiness, she will automatically arch her back, deflect her tail and stand rigid to allow an aroused male to mount. Now, Rockefeller University researchers have figured out the precise chemical and physical mechanism in a group of brain cells that controls this swayback posture, a reflex called lordosis that signals one of life’s most complex yet primitive instincts — the need for sex.
New brain cells implicated in machinery of cannabinoid signaling
The brain cells called astrocytes, and not just neurons, are sensitive to the substances called cannabinoids—the active chemicals in marijuana.
Protein protects embryonic stem cells' versatility and self-renewal
A protein known as REST blocks the expression of a microRNA that prevents embryonic stem cells from reproducing themselves and causes them to differentiate into specific cell types, scientists at The University of Texas M. D. Anderson Cancer Center report in the journal Nature.
Language of a fly proves surprising
A group of researchers has developed a novel way to view the world through the eyes of a common fly and partially decode the insect’s reactions to changes in the world around it. The research fundamentally alters earlier beliefs about how neural networks function and could provide the basis for intelligent computers that mimic biological processes.

News discussion:

Medicine & Health news