Health Sciences Report Winter 2005

Research Headlines
Discoveries from the U of U Reported in Leading National Journals

A 'Dimmer Switch' for Genes

When flexible, randomly structured regions of a protein molecule, believed to be only minor players, are modifi ed, they become important in turning genes on and off in a way that resembles a dimmer switch.

The discovery by Barbara J. Graves, Ph.D., professor and chair of the medical school's Department of Oncological Sciences, and doctoral student Miles Pufall was published in the July 1 issue of Science.

At the University's Huntsman Cancer Institute (HCI), the researchers studied Ets-1, a protein known as a transcription factor that helps read genetic information. Without the right information, cells may, as in the case of cancer, grow out of control. One way proteins are controlled occurs after a cell creates a protein: the protein can acquire post-translational modifi cations.

Graves and Pufall studied phosphate additions. Previously, these modifi cations had been shown to build up on proteins until a certain number accumulated. They'd been described as a sharp on/off switch of protein activity.

"What we found was that each time we added a phosphate to a particular unstructured region of Ets-1, there was an effect on the protein's ability to bind to a gene. Binding was weakened, but it was gradual," said Graves. "It behaved the way a dimmer switch does to regulate lighting."

It was known that proteins have regions with parts that are fixed in space with a definite structure, which were thought to do most of the work, in addition to parts that are randomly positioned in space and serve only minor roles. However, the researchers discovered that unstructured regions of the Ets-1 protein were affecting the structured regions. The fi ndings have long-term implications, because any protein can be organized with structured and unstructured regions that work together.

Co-authors include Mary L. Nelson, HCI doctoral student, and scientists from the University of British Columbia and University of Toronto.

Thinking Outside the Nucleus

The transformation of pre-mRNA into mature mRNA, a key process in gene regulation, has been shown to occur in human platelets: unique cells that don't have a nucleus, so were thought incapable of turning on genes and synthesizing proteins.

This discovery was reported in the Aug. 12 edition of Cell by a research team from the University's Program in Human Molecular Biology and Genetics (HMBG) at Eccles Institute of Human Genetics.

mRNAs are molecules that encode genetic information from DNA and direct the synthesis of proteins. Scientists have thought that splicing, the transformation of pre-mRNA into mature mRNA, happens only in a cell's nucleus. The U researchers found, however, that splicing also takes place in the cytoplasm of activated platelets.

Platelets are abundant cells that circulate in human blood. Their primary role is to form "plugs" that stop bleeding from injured vessels; they also release factors that promote tissue repair and mediate infl ammation. When platelets malfunction, they can cause clots that contribute to life-threatening disease. Too few platelets can result in hemorrhaging.

In blood platelets, the researchers also identifi ed pre-mRNA that codes for Interleukin 1. (IL-1.), a protein that plays major roles in infl ammation, defense against infection, organ development, and disease. When platelets are activated in response to injury, the IL-1. pre-mRNA is processed into mature mRNA, which then directs production of the critical infl ammatory protein.

The discoveries have immediate clinical relevance, said Guy A. Zimmerman, M.D., professor of internal medicine, HMBG director, and a study co-author. "This gives new insight into how disease mechanisms work. If we could learn how to interrupt it, we might be able to turn down the infl ammatory process."

In addition to experiments with circulating platelets from the blood of volunteers, Andrew S. Weyrich, Ph.D., research associate professor of internal medicine and study director, devised a way to induce human stem cells to differentiate into megakaryocytes, or parent cells of platelets, that could be grown in the lab, which was critical to the discoveries.

Co-first authors of the study are: the late Melvin M. Denis, M.D., Ph.D., and Neal D. Tolley, Eccles Institute of Human Genetics.

Stomach Problems

Over-the-counter doses of nonsteroidal anti-inflammatory drugs ibuprofen and naproxen can increase the risk of gastrointestinal (GI) complications, perforations in the stomach lining, ulcers, and GI bleeds, according to a review of a national electronic database of 3.2 million patient health records.

Joseph Biskupiak, Ph.D., the study's lead author and research associate professor of pharmacotherapy at the U College of Pharmacy, presented the data at the annual scientific meeting of the American College of Gastroenterology in Honolulu Nov. 2.

Patients taking low-dose aspirin at the same time as ibuprofen or naproxen have an even greater likelihood for GI events than those who do not take aspirin, according to the analysis.

A New Turn-on for Genes

A special type of molecular structure, a nucleosome bearing a protein called Htz1, has been discovered, which helps keep genes properly turned off until the structure is ejected from those genes in a regulated manner to help turn the genes on, reported Brad Cairns, Ph.D., lead scientist on the study reported in the Oct. 21 issue of Cell.

"We are beginning to understand how gene activation and repression is altered in cancer cells, and how that leads to tumor growth," said Cairns, associate professor of oncological sciences at the School of Medicine, an investigator at the U Huntsman Cancer Institute, and an investigator with the Howard Hughes Medical Institute. "However, the design of targeted treatments that can correct these alterations will require a deep knowledge of the basic cellular mechanisms that regulate gene expression."

Obesity and Heart Failure

U researchers have found a defective respiratory capacity in the hearts of obese mice, which ultimately may contribute to an increased risk of heart failure, according to an article in the Oct. 25 issue of Circulation.

Obesity is a risk factor for cardiovascular disease and is strongly associated with insulin resistance and type 2 diabetes, although the mechanisms underlying the association are unclear.

Researchers in the lab of E. Dale Abel, M.D., Ph.D., U associate professor of internal medicine and biochemistry, and an investigator in the Program in Human Molecular Biology and Genetics, found that mitochondrial dysfunction developed in the hearts of a mouse model of severe obesity and insulin resistance. The dysfunction may contribute to reduced cardiac performance and efficiency. Future studies are needed to determine whether weight loss will reverse these dysfunctions. ...More Information

Budding Images

U researchers who produced the first high-resolution images of the protein that the AIDS virus must use to replicate and spread through the human body see the images as a possible fi rst step toward new drugs against the disease.

The first structures of the VPS4 protein have shed light on its role as HIV-1 "buds" or escapes from cells. "By understanding how the virus buds from a cell, we might be able to develop drugs to inhibit the virus from spreading," said Wesley I. Sundquist, Ph.D., professor of biochemistry and head of the research team that published their findings in the Oct. 4 edition of the European Molecular Biology Organization (EMBO) Journal and the Sept. 20 online edition of the Proceedings of the National Academy of Sciences.

Rhythm Gene

In nematode worms, a gene that controls fundamental rhythms, including swallowing food, laying eggs, and pooping, has been discovered by U of U biologists.

"The same gene products that control the fundamental processes of life in mammals also are found in the worm, so our study suggests this gene and related genes may have critical roles in controlling rhythmic behaviors in humans and other animals," said Andres Villu Maricq, M.D., Ph.D., professor of biology and a member of the Brain Institute at the U of U.

The discovery was reported in the Oct. 7 issue of Cell. The U study deals with ultradian rhythms that control body functions, such as the heart rate, breathing, swallowing, and contraction of the intestines.

TZDs and Edema

Tianxin Yang, M.D., Ph.D., U associate professor of internal medicine and staff physician at the George E. Wahlen Department of Veterans Affairs Medical Center in Salt Lake City, discovered how a major anti-diabetes drug, thiazolidinediones (TZDs), causes edema.

In the Proceedings of the National Academy of Sciences, published online June 13, he reported that, when TZD activates a nuclear receptor in the collecting duct in the kidney, which helps sensitize the body to insulin, it serves as a mechanism for fluid retention, or edema.

Yang also discovered that the pathway critical to fl uid metabolism may help in understanding fundamental mechanisms of blood pressure control.

Breast Cancer Risk Factor

Women whose mother, sister, or daughter have lobular breast cancer are two-and-a-half times more likely to develop any type of breast cancer and more than four times as likely to be diagnosed with lobular breast cancer, according to a U study published online last June in the International Journal of Cancer.

Previous research on the familial risk of breast cancer had been unclear whether increased risks differ by the type of breast cancer, according to corresponding author Kristina Allen-Brady, U graduate student in medical informatics.

U of U researchers conducted a population-based analysis of the familial nature of lobular breast cancer, found in the milk-producing glands. Results suggest that at-risk women may need more thorough screening, such as an MRI, to detect the disease in its early stages.

Maturity Gene

The discovery that a fruit fly gene is crucial for determining when juveniles begin to mature into adults, and how the transformation initially proceeds, may help researchers understand how cute children become rude teenagers.

The finding was published in the June 3 issue of Cell. Carl Thummel, Ph.D., U professor of human genetics and an investigator with the Howard Hughes Medical Institute, is principal author.

He discovered that when the DHR4 gene is disabled, fruit flies prematurely begin metamorphosis from an immature larva to a sexually active adult. The flies are abnormally small and die as they enter adulthood. The process is relevant to people, because insect metamorphosis is analogous to the transformation of a human from a juvenile to sexually active reproductive adult.

Tumor Growth

Researchers at the University's Huntsman Cancer Institute discovered an enzyme that, when inhibited, appears to reduce the incidence of Rasinduced tumors in mice.

"The implication is that a drug therapy could be developed to reduce tumors caused by Ras without significant side effects," said Matthew K. Topham, M.D., assistant professor of internal medicine and lead investigator on the study, published in the May 9 issue of the Proceedings of the National Academy of Sciences Online Early Edition.

When mutated, the gene Ras has been shown to promote the growth of cancers in the pancreas, colon, and lung, as well as thyroid cancer and leukemia. The researchers studied a type of enzyme called diacylglycerol kinase (DGK). Mice with an activated Ras gene, but an absent DGK iota gene, developed few tumors.

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