Study Shows Protein Complex May Play Role In Preventing Many Forms Of Cancer

Main Category: Cancer / Oncology
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Article Date: 08 May 2013 - 0:00 PDT Current ratings for:
Study Shows Protein Complex May Play Role In Preventing Many Forms Of Cancer

Researchers at the Stanford University School of Medicine have identified a group of proteins that are mutated in about one-fifth of all human cancers. The finding suggests that the proteins, which are members of a protein complex that affects how DNA is packaged in cells, work to suppress the development of tumors in many types of tissues.

The broad reach of the effect of mutations in the complex, called BAF, rivals that of another well-known tumor suppressor called p53. It also furthers a growing notion that these so-called chromatin-regulatory complexes may function as much more than mere cellular housekeepers.

"Although we knew that this complex was likely to play a role in preventing cancer, we didn't realize how extensive it would be," said postdoctoral scholar Cigall Kadoch, PhD. "It's often been thought that these complexes play supportive, maintenance-like roles in the cell. But this is really changing now."

Kadoch shares lead authorship of the study with postdoctoral scholar Diana Hargreaves, PhD. Gerald Crabtree, MD, professor of developmental biology and of pathology, is the senior author of the study, which was published online in Nature Genetics.

Chromatin-regulatory complexes work to keep DNA tightly condensed, while also granting temporary access to certain portions for replication or to allow the expression of genes necessary for the growth or function of the cell.

Members of Crabtree's laboratory have been interested in BAF complexes and their function for many years. Recently, they reported in the journal Nature that switching subunits within these complexes can convert human fibroblasts to neurons, which points to their instructive role in development and, possibly, cancer.

"Somehow these chromatin-regulatory complexes manage to compress nearly two yards of DNA into a nucleus about one one-thousandth the size of a pinhead," said Crabtree, who is also a member of the Stanford Cancer Institute and a Howard Hughes Medical Institute investigator. "And they do this without compromising the ability of the DNA to be replicated and selectively expressed in different tissues - all without tangling. In 1994 we reported that complexes of this type were likely to be tumor suppressors. Here we show that they are mutated in nearly 20 percent of all human malignancies thus far examined."

The researchers combined biochemical experiments with the data mining of 44 pre-existing studies to come to their conclusions, which would not have been possible without the advent of highly accurate, genome-wide DNA sequencing of individual human tumor samples. Interestingly, mutations to certain subunits, or particular combinations of mutations in the complex's many subunits, seem to herald the development of specific types of cancer - favoring the development of ovarian versus colon cancer, for example.

The importance of the BAF complex as a tumor suppressor is further emphasized by the fact that, in some cases, a mutation in one subunit is sufficient to initiate cancer development.

"For example," said Kadoch, "a type of mutation called a chromosomal translocation in the gene encoding one of these newly identified subunits, SS18, is known to be the hallmark of a cancer called synovial sarcoma. It is clearly the driving oncogenic event and very often the sole genomic abnormality in these cancers." Kadoch and Crabtree published a study in March in Cell uncovering the mechanism and functional consequences of BAF complex perturbation in synovial sarcoma.

The startling prevalence of mutations in the BAF complex was discovered when Kadoch conducted a series of experiments to determine exactly which proteins in the cell were true subunits of the complex. (The exact protein composition of the large complex varies among cell types and species.) Kadoch used an antibody that recognized one core component to purify intact BAF complexes in various cell types, including embryonic stem cells and skin, nerve and other cells. She then analyzed the various proteins isolated by the technique.

Using this method, Kadoch identified seven proteins previously unknown to be BAF components. She and Hargreaves then turned to previously published studies in which the DNA from a variety of human tumors had been sequenced to determine how frequently any of the members of the complex were mutated.

The results, once the newly discovered members were included, were surprising: 19.6 percent of all human tumors displayed a mutation in at least one of the complex's subunits. In addition, for some types of cancers (such as synovial sarcoma), every individual tumor sample examined had a mutation in a BAF subunit. The results suggest that the BAF complex, when unmutated, plays an important protective role against the development of cancer in many different tissues.

The researchers are now focused on learning how the mutations affect the tumor-suppressing activity of the BAF complex.

"We certainly want to further our understanding of the mechanism behind these findings," said Hargreaves. "Do they promote cancer development by inhibiting the proper progression of the cell cycle? Or perhaps they affect how the complex is positioned on the DNA. We'd like to determine how to recapitulate some of these mutations experimentally to see what types of defects they introduce into the complex."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. Other Stanford authors of the study include postdoctoral scholar Courtney Hodges, PhD, and former lab members Laura Elias, PhD, and Lena Ho, PhD.

The research was funded by the National Institutes of Health (grants NS046789, CA163915 and F32HD072627), the National Science Foundation, the Howard Hughes Medical Institute and the Helen Hay Whitney Foundation.

Stanford University Medical Center

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Expert Advice on Preventing Headaches

How to Prevent Headaches - ABC News Hot Topics: Powerball Winner?$590 Million Jackpot?Youngest Manson Follower HomeU.S.WorldPoliticsVideoInvestigativeHealthEntertainmentMoneyTechTravelHealth HeadlinesFor a Healthier Diet, Go WildAlcohol Could Get Nutrition Labels Expert Advice on Preventing HeadachesNew Hope for Kids With Food AllergiesLawyers Push for Transplant Rule...WATCH VIDEO: Health »Obese Woman Tattoos Weight Goal on...H&M CEO: Our Models Are Too...More Health Headlines'Low-T' Testosterone Ads Leading to...Michael Douglas' Throat Cancer Tied to...The 'Prancercise' Craze and Other...Eye Lift Payments Raising EyebrowsSaudi Teen Contracts Deadly Virus Home> Health>ABC News OnCall+ Wellness CenterHow to Prevent HeadachesBy HALLIE LEVINE SKLAR
Health.comJune 5, 2013

ABCNEWS.com

Ninety-nine percent of us will endure a headache at some point—no shocker to migraine sufferers or anyone who has wanted to pull off her throbbing head after a stressful day. "Women are more likely than men to get migraines specifically, possibly because of hormonal triggers," says Stewart Tepper, MD, a headache medicine specialist at the Cleveland Clinic. Happily, there's new information out there about triggers and cures. Follow this expert advice and that pesky pain will no longer be such a...headache.

How to Prevent HeadachesTension Headache

The Lowdown

Blame stress—which can cause muscle tightness and pain in your neck and head—for this most common kind of headache. Fatigue, a lack of exercise and even infrequent eating can also make your body stiffen up. Experts say some sufferers with overactive pain receptors may be more prone to discomfort.

What It Feels Like

A dull pain that stretches across your forehead and/or the sides and back of your head. Pain often increases gradually, beginning around midday. Luckily, says Dr. Tepper, "it's rarely debilitating."

The Fix

Pop a pain reliever, like Advil or Tylenol, at first symptoms, but not more than 10 times a month (you can develop rebound headaches from overuse). To prevent tension pain, exercise regularly, get enough sleep, eat small, frequent meals and practice relaxation techniques, like yoga. Research shows massage eases tension headaches: Rub tender spots on your forehead and scalp with thumb and fingertips, suggests Boulder, Colo., massage and spinal-reflex therapist Maureen Moon. If nothing works, a headache specialist may recommend an antidepressant to regulate pain receptors.

What Kind of Headache Do You Have?

How to Prevent HeadachesMigraine

The Lowdown

About 18 percent of women get migraines—the most crippling kind of headache—per the National Headache Foundation. They can be tied to the start of your period; about 60 percent of female migraineurs (as they're called) experience them then, due to a plunge in hormones, says Mark Green, MD, director of headache and pain medicine at Icahn School of Medicine at Mount Sinai Hospital in New York City. Most women report that their migraines go away or weaken postmenopause.

What It Feels Like

An intense, one-sided, throbbing pain that may or may not be accompanied by nausea, vomiting or sensitivity to bright lights and sounds. It often worsens with physical activity. The pain can last for days and be so severe that you may be reduced to lying in the dark. (If your pain is shorter-lived, you may actually have a cluster headache, especially if your eyes also tear up.) About 20 percent of sufferers have an aura—visual disturbances such as flashing lights and blind spots. Common triggers include dehydration; beer and red wine; aged cheeses; chocolate; skipping meals; strong smells such as perfume; or changes in sleeping patterns.

The Fix

A neurologist may suggest drugs called triptans—the first line of prescription treatment for migraines, Dr. Tepper says (and for cluster headaches). Once you have a medical plan, a doctor may have you keep a headache diary to pinpoint triggers, and recommend over-the-counter supplements, like magnesium (deficiencies have been linked to migraines) or the anti-inflammatory butterbur. If you get migraines more than twice a week, consider talking to your doctor about trying a beta-blocker.

18 Signs You're Having a Migraine

How to Prevent HeadachesSinus pain

The Lowdown

Swelling and inflammation of your sinuses—the small, hollow spaces around your eyes, cheeks and nose—can lead to facial and head pain, especially during allergy seasons. That swelling, called sinusitis, can also stem from bacterial or fungal infections or, most often, the common cold. Surprisingly, what most people think of as sinus headaches are migraines about 90 percent of the time, one study suggests.

What It Feels Like

"There's heaviness in your sinuses that stays until the infection or blockage is relieved—it doesn't come and go, like a migraine or tension headache," explains Scott Stringer, MD, chair of the department of otolaryngology at the University of Mississippi Medical Center. You'll also have a stuffy or runny nose with yellow or greenish gook, and, if it's a bacterial infection, a fever.

The Fix

Antibiotics can put an end to bacterial sinusitis, or you can pick up over-the-counter decongestants and saline nasal sprays to relieve symptoms. Chronic sinusitis—lasting for more than 12 weeks—can usually be treated with a prescription steroid nasal spray; if it's allergy-related, treatments like antihistamines and allergy shots can help, says Dr. Stringer. If those don't work and your symptoms are severe, you may need surgery to correct a structural problem like nasal polyps or to enlarge your sinus openings.

Products to Help You Find Sinus Relief

This article originally appeared on Health.com.

***

More from Health.com:

Headache-Proof Your Home

11 Surprising Headache Triggers

Get Headaches? Smart Ways to Deal

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